U.S. patent application number 15/411506 was filed with the patent office on 2018-01-04 for nucleoside phosphoramidate prodrugs.
The applicant listed for this patent is Gilead Pharmasset LLC. Invention is credited to Jinfa Du, Dhanapalan Nagarathnam, Michael Joseph Sofia, Peiyuan Wang.
Application Number | 20180000855 15/411506 |
Document ID | / |
Family ID | 39808855 |
Filed Date | 2018-01-04 |
United States Patent
Application |
20180000855 |
Kind Code |
A1 |
Du; Jinfa ; et al. |
January 4, 2018 |
NUCLEOSIDE PHOSPHORAMIDATE PRODRUGS
Abstract
Disclosed herein are phosphoramidate prodrugs of nucleoside
derivatives for the treatment of viral infections in mammals, which
is a compound, its stereoisomer, salt (acid or basic addition
salt), hydrate, solvate, or crystalline form thereof, represented
by the following structure: ##STR00001## Also disclosed are methods
of treatment, uses, and processes for preparing each of which
utilize the compound represented by formula I.
Inventors: |
Du; Jinfa; (Redwood City,
CA) ; Nagarathnam; Dhanapalan; (Bethany, CT) ;
Sofia; Michael Joseph; (Doylestown, PA) ; Wang;
Peiyuan; (San Mateo, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Pharmasset LLC |
Foster City |
CA |
US |
|
|
Family ID: |
39808855 |
Appl. No.: |
15/411506 |
Filed: |
January 20, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/7068 20130101;
C07H 19/06 20130101; A61P 43/00 20180101; A61P 31/12 20180101; A61P
31/20 20180101; A61K 45/06 20130101; C07D 417/14 20130101; C07H
19/10 20130101; C07H 19/20 20130101; A61K 31/7072 20130101; A61K
31/706 20130101; A61P 31/16 20180101; A61K 31/7076 20130101; A61K
31/7064 20130101; C07H 17/02 20130101; A61P 31/00 20180101; Y02A
50/30 20180101; Y02A 50/463 20180101; A61P 31/14 20180101; C07H
19/073 20130101; C07H 19/04 20130101; A61P 31/18 20180101 |
International
Class: |
A61K 31/7072 20060101
A61K031/7072; C07H 19/06 20060101 C07H019/06; A61K 45/06 20060101
A61K045/06 |
Claims
1. A compound of formula IA: ##STR00061## or a stereoisomer
thereof, wherein: R.sup.1 is naphthyl; R.sup.2 is H or C.sub.1-10
alkyl, or R.sup.2 together with R.sup.3a or R.sup.3b are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where n is 2 to 4; R.sup.3a and R.sup.3b
are (i) independently selected from H, C.sub.1-10 alkyl,
cycloalkyl, --(CH.sub.2).sub.c(NR.sup.3').sub.2, C.sub.1-6
hydroxyalkyl, --CH.sub.2SH, --(CH.sub.2).sub.2S(O).sub.dMe,
--(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, (1H-indol-3-yl)methyl,
(1H-imidazol-4-yl)methyl, --(CH.sub.2).sub.eCOR.sup.3'', aryl and
aryl C.sub.1-3 alkyl, said aryl groups optionally substituted with
a group selected from hydroxyl, C.sub.1-10 alkyl, C.sub.1-6 alkoxy,
halogen, nitro and cyano; (ii) R.sup.3a and R.sup.3b both are
C.sub.1-6 alkyl; (iii) R.sup.3a and R.sup.3b together are
(CH.sub.2).sub.f so as to form a spiro ring; (iv) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms;
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 2 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3 is --OR' or
--N(R.sup.3').sub.2; (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
--CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H, where R.sup.3' is independently
H or alkyl and R.sup.3'' is --OR' or --N(R.sup.3').sub.2; R.sup.4
is H or C.sub.1-10 alkyl optionally substituted with a lower alkyl,
alkoxy, di(lower alkyl)amino, or halogen, C.sub.1-10 haloalkyl,
C.sub.3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,
aminoacyl, optionally substituted aryl or optionally substituted
heteroaryl; R.sup.5 is CH.sub.2CN, CH.sub.2NH.sub.2,
CH.sub.2NHCH.sub.3 or CH.sub.2N(CH.sub.3).sub.2; R.sup.6 is H,
CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, F or CN; X is H, OH,
OCH.sub.3, halogen, NH.sub.2, or N.sub.3; Y is OH, H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, vinyl, N.sub.3, CN,
Cl, Br, F, I, NO.sub.2, OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.1-4
alkyl), OC(O)O(C.sub.2-4 alkynyl), OC(O)O(C.sub.2-4 alkenyl),
OC.sub.1-10 haloalkyl, O(aminoacyl), acyl), O(C.sub.1-4 alkyl),
O(C.sub.2-4 alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl),
S(C.sub.2-4 alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl),
SO(C.sub.1-4 alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-18 acyl).sub.2, wherein alkyl,
alkynyl, alkenyl and vinyl are optionally substituted by N.sub.3,
CN, one to three halogen, NO.sub.2, C(O)O(C.sub.1-4 alkyl),
C(O)O(C.sub.1-4 alkyl), C(O)O(C.sub.2-4 alkynyl), C(O)O(C.sub.2-4
alkenyl), O(C.sub.1-4 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4
alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4
alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4
alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2 or N(C.sub.1-4 acyl).sub.2; R.sup.7,
R.sup.8 and R.sup.9 are independently H, F, Cl, Br, I, OH, OR', SH,
SR', NH.sub.2, NHR', NR'.sub.2, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 haloalkenyl, C.sub.2-6
alkynyl, C.sub.2-6 haloalkynyl, C.sub.1-6 alkoxy, C.sub.1-6
haloalkoxy, CO.sub.2H, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R', wherein R' is an
optionally substituted alkyl, an optionally substituted cycloalkyl,
an optionally substituted C.sub.2-6 alkynyl, an optionally
substituted C.sub.2-6 alkenyl, or an optionally substituted acyl,
or in the instance of NR'.sub.2, each R' comprise at least one C
atom that are joined to form a heterocycle comprising at least two
carbon atoms; and
2. The compound of claim 1 represented by formula IB: ##STR00062##
or a stereoisomer thereof.
3. The compound of claim 2, wherein R.sup.2 is H or C.sub.1-10
alkyl.
4. The compound of claim 2, wherein one of R.sup.3a and R.sup.3b is
H and the other is C.sub.1-10 alkyl.
5. The compound of claim 2, wherein R.sup.4 is C.sub.1-10
alkyl.
6. The compound of claim 2, wherein R.sup.6 is methyl.
7. The compound of claim 2, wherein each of R.sup.7 and R.sup.8 is
H.
8. The compound of claim 2, wherein X is halogen.
9. The compound of claim 2, wherein Y is OH.
10. The compound of claim 2, wherein the compound is represented by
formula IC: ##STR00063## or a stereoisomer thereof.
11. The compound of claim 10, wherein R.sup.2 is H.
12. The compound of claim 10 represented by formula ID:
##STR00064## or a stereoisomer thereof.
13. The compound of claim 12, wherein R.sup.4 is .sup.iPr,
.sup.nPr, .sup.nBu, 2-butyl, .sup.tBu or benzyl.
14. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable excipient.
15. A method of treating HCV comprising administering a
therapeutically effective amount of a compound according to claim 1
to a human in need thereof.
16. The method of claim 15 further comprising administering to the
human a therapeutically effective amount of a second antiviral
agent.
17. The method of claim 16 wherein the second antiviral agent is an
NS5A inhibitor.
18. The method of claim 16 wherein the second antiviral agent is an
NS3 protease inhibitor.
19. The method of claim 15 further comprising administering to the
human subject therapeutically effective amounts of an NS5A
inhibitor and an NS3 protease inhibitor.
Description
FIELD OF INVENTION
[0001] The present invention pertains to nucleoside
phosphoramidates and their use as agents for treating viral
diseases. These compounds are inhibitors of RNA-dependent RNA viral
replication and are useful as inhibitors of HCV NS5B polymerase, as
inhibitors of HCV replication and for treatment of hepatitis C
infection in mammals. The invention provides novel chemical
compounds, and the use of these compounds alone or in combination
with other antiviral agents for treating HCV infection.
BACKGROUND
[0002] Hepatitis C virus (HCV) infection is a major health problem
that leads to chronic liver disease, such as cirrhosis and
hepatocellular carcinoma, in a substantial number of infected
individuals, estimated to be 2-15% of the world's population. There
are an estimated 4.5 million infected people in the United States
alone, according to the U.S. Center for Disease Control. According
to the World Health Organization, there are more than 200 million
infected individuals worldwide, with at least 3 to 4 million people
being infected each year. Once infected, about 20% of people clear
the virus, but the rest can harbor HCV the rest of their lives. Ten
to twenty percent of chronically infected individuals eventually
develop liver-destroying cirrhosis or cancer. The viral disease is
transmitted parenterally by contaminated blood and blood products,
contaminated needles, or sexually and vertically from infected
mothers or carrier mothers to their offspring. Current treatments
for HCV infection, which are restricted to immunotherapy with
recombinant interferon-.alpha. alone or in combination with the
nucleoside analog ribavirin, are of limited clinical benefit.
Moreover, there is no established vaccine for HCV. Consequently,
there is an urgent need for improved therapeutic agents that
effectively combat chronic HCV infection.
[0003] The HCV virion is an enveloped positive-strand RNA virus
with a single oligoribonucleotide genomic sequence of about 9600
bases which encodes a polyprotein of about 3,010 amino acids. The
protein products of the HCV gene consist of the structural proteins
C, E1, and E2, and the non-structural proteins NS2, NS3, NS4A and
NS4B, and NS5A and NS5B. The nonstructural (NS) proteins are
believed to provide the catalytic machinery for viral replication.
The NS3 protease releases NS5B, the RNA-dependent RNA polymerase
from the polyprotein chain. HCV NS5B polymerase is required for the
synthesis of a double-stranded RNA from a single-stranded viral RNA
that serves as a template in the replication cycle of HCV.
Therefore, NS5B polymerase is considered to be an essential
component in the HCV replication complex (K. Ishi, et al,
Heptology, 1999, 29: 1227-1235; V. Lohmann, et al., Virology, 1998,
249: 108-118). Inhibition of HCV NS5B polymerase prevents formation
of the double-stranded HCV RNA and therefore constitutes an
attractive approach to the development of HCV-specific antiviral
therapies.
[0004] HCV belongs to a much larger family of viruses that share
many common features.
[0005] Flaviviridae Viruses
[0006] The Flaviviridae family of viruses comprises at least three
distinct genera: pestiviruses, which cause disease in cattle and
pigs; flavivruses, which are the primary cause of diseases such as
dengue fever and yellow fever; and hepaciviruses, whose sole member
is HCV. The flavivirus genus includes more than 68 members
separated into groups on the basis of serological relatedness
(Calisher et al., J. Gen. Virol, 1993, 70, 37-43). Clinical
symptoms vary and include fever, encephalitis and hemorrhagic fever
(Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley,
P. M., Lippincott-Raven Publishers, Philadelphia, Pa., 1996,
Chapter 31, 931-959). Flaviviruses of global concern that are
associated with human disease include the Dengue Hemorrhagic Fever
viruses (DHF), yellow fever virus, shock syndrome and Japanese
encephalitis virus (Halstead, S. B., Rev. Infect. Dis., 1984, 6,
251-264; Halstead, S. B., Science, 239:476-481, 1988; Monath, T.
P., New Eng. J. Med, 1988, 319, 64 1-643).
[0007] The pestivirus genus includes bovine viral diarrhea virus
(BVDV), classical swine fever virus (CSFV, also called hog cholera
virus) and border disease virus (BDV) of sheep (Moennig, V. et al.
Adv. Vir. Res. 1992, 41, 53-98). Pestivirus infections of
domesticated livestock (cattle, pigs and sheep) cause significant
economic losses worldwide. BVDV causes mucosal disease in cattle
and is of significant economic importance to the livestock industry
(Meyers, G. and Thiel, H. J., Advances in Virus Research, 1996, 47,
53-118; Moennig V., et al, Adv. Vir. Res. 1992, 41, 53-98). Human
pestiviruses have not been as extensively characterized as the
animal pestiviruses. However, serological surveys indicate
considerable pestivirus exposure in humans.
[0008] Pestiviruses and hepaciviruses are closely related virus
groups within the Flaviviridae family. Other closely related
viruses in this family include the GB virus A, GB virus A-like
agents, GB virus-B and GB virus-C (also called hepatitis G virus,
HGV). The hepacivirus group (hepatitis C virus; HCV) consists of a
number of closely related but genotypically distinguishable viruses
that infect humans. There are at least 6 HCV genotypes and more
than 50 subtypes. Due to the similarities between pestiviruses and
hepaciviruses, combined with the poor ability of hepaciviruses to
grow efficiently in cell culture, bovine viral diarrhea virus
(BVDV) is often used as a surrogate to study the HCV virus.
[0009] The genetic organization of pestiviruses and hepaciviruses
is very similar. These positive stranded RNA viruses possess a
single large open reading frame (ORF) encoding all the viral
proteins necessary for virus replication. These proteins are
expressed as a polyprotein that is co- and post-translationally
processed by both cellular and virus-encoded proteinases to yield
the mature viral proteins. The viral proteins responsible for the
replication of the viral genome RNA are located within
approximately the carboxy-terminal. Two-thirds of the ORF are
termed nonstructural (NS) proteins. The genetic organization and
polyprotein processing of the nonstructural protein portion of the
ORF for pestiviruses and hepaciviruses is very similar. For both
the pestiviruses and hepaciviruses, the mature nonstructural (NS)
proteins, in sequential order from the amino-terminus of the
nonstructural protein coding region to the carboxy-terminus of the
ORF, consist of p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B.
[0010] The NS proteins of pestiviruses and hepaciviruses share
sequence domains that are characteristic of specific protein
functions. For example, the NS3 proteins of viruses in both groups
possess amino acid sequence motifs characteristic of serine
proteinases and of helicases (Gorbalenya et al., Nature, 1988, 333,
22; Bazan and Fletterick Virology, 1989, 171, 637-639; Gorbalenya
et al., Nucleic Acid Res., 1989, 17, 3889-3897). Similarly, the
NS5B proteins of pestiviruses and hepaciviruses have the motifs
characteristic of RNA-directed RNA polymerases (Koonin, E. V. and
Dolja, V. V., Crir. Rev. Biochem. Molec. Biol. 1993, 28,
375-430).
[0011] The actual roles and functions of the NS proteins of
pestiviruses and hepaciviruses in the lifecycle of the viruses are
directly analogous. In both cases, the NS3 serine proteinase is
responsible for all proteolytic processing of polyprotein
precursors downstream of its position in the ORF (Wiskerchen and
Collett, Virology, 1991, 184, 341-350; Bartenschlager et al., J.
Virol. 1993, 67, 3835-3844; Eckart et al. Biochem. Biophys. Res.
Comm. 1993, 192, 399-406; Grakoui et al., J. Virol. 1993, 67,
2832-2843; Grakoui et al., Proc. Natl. Acad Sci. USA 1993, 90,
10583-10587; Hijikata et al., J. Virol. 1993, 67, 4665-4675; Tome
et al., J. Virol., 1993, 67, 4017-4026). The NS4A protein, in both
cases, acts as a cofactor with the NS3 serine protease
(Bartenschlager et al., J. Virol. 1994, 68, 5045-5055; Failla et
al., J. Virol. 1994, 68, 3753-3760; Xu et al., J. Virol., 1997,
71:53 12-5322). The NS3 protein of both viruses also functions as a
helicase (Kim et al., Biochem. Biophys. Res. Comm., 1995, 215,
160-166; Jin and Peterson, Arch. Biochem. Biophys., 1995, 323,
47-53; Warrener and Collett, J. Virol. 1995, 69, 1720-1726).
Finally, the NS5B proteins of pestiviruses and hepaciviruses have
the predicted RNA-directed RNA polymerases activity (Behrens et
al., EMBO, 1996, 15, 12-22; Lechmann et al., J. Virol., 1997, 71,
8416-8428; Yuan et al., Biochem. Biophys. Res. Comm. 1997, 232,
231-235; Hagedorn, PCT WO 97/12033; Zhong et al, J. Virol., 1998,
72, 9365-9369).
[0012] Currently, there are limited treatment options for
individuals infected with hepatitis C virus. The current approved
therapeutic option is the use of immunotherapy with recombinant
interferon-.alpha. alone or in combination with the nucleoside
analog ribavirin. This therapy is limited in its clinical
effectiveness and only 50% of treated patients respond to therapy.
Therefore, there is significant need for more effective and novel
therapies to address the unmet medical need posed by HCV
infection.
[0013] A number of potential molecular targets for drug development
of direct acting antivirals as anti-HCV therapeutics have now been
identified including, but not limited to, the NS2-NS3 autoprotease,
the N3 protease, the N3 helicase and the NS5B polymerase. The
RNA-dependent RNA polymerase is absolutely essential for
replication of the single-stranded, positive sense, RNA genome and
this enzyme has elicited significant interest among medicinal
chemists.
[0014] Inhibitors of HCV NS5B as potential therapies for HCV
infection have been reviewed: Tan, S.-L., et al., Nature Rev. Drug
Discov., 2002, 1, 867-881; Walker, M. P. et al., Exp. Opin.
Investigational Drugs, 2003, 12, 1269-1280; Ni, Z-J., et al.,
Current Opinion in Drug Discovery and Development, 2004, 7,
446-459; Beaulieu, P. L., et al., Current Opinion in
Investigational Drugs, 2004, 5, 838-850; Wu, J., et al., Current
Drug Targets-Infectious Disorders, 2003, 3, 207-219; Griffith, R.
C., et al, Annual Reports in Medicinal Chemistry, 2004, 39,
223-237; Carrol, S., et al., Infectious Disorders-Drug Targets,
2006, 6, 17-29. The potential for the emergence of resistant HCV
strains and the need to identify agents with broad genotype
coverage supports the need for continuing efforts to identify novel
and more effective nucleosides as HCV NS5B inhibitors.
[0015] Nucleoside inhibitors of NS5B polymerase can act either as a
non-natural substrate that results in chain termination or as a
competitive inhibitor which competes with nucleotide binding to the
polymerase. To function as a chain terminator the nucleoside analog
must be taken up by the cell and converted in vivo to a
triphosphate to compete for the polymerase nucleotide binding site.
This conversion to the triphosphate is commonly mediated by
cellular kinases which imparts additional structural requirements
on a potential nucleoside polymerase inhibitor. Unfortunately, this
limits the direct evaluation of nucleosides as inhibitors of HCV
replication to cell-based assays capable of in situ
phosphorylation.
[0016] In some cases, the biological activity of a nucleoside is
hampered by its poor substrate characteristics for one or more of
the kinases needed to convert it to the active triphosphate form.
Formation of the monophosphate by a nucleoside kinase is generally
viewed as the rate limiting step of the three phosphorylation
events. To circumvent the need for the initial phosphorylation step
in the metabolism of a nucleoside to the active triphosphate
analog, the preparation of stable phosphate prodrugs has been
reported. Nucleoside phosphoramidate prodrugs have been shown to be
precursors of the active nucleoside triphosphate and to inhibit
viral replication when administered to viral infected whole cells
(McGuigan, C., et al., J. Med. Chem., 1996, 39, 1748-1753; Valette,
G., et al., J. Med. Chem., 1996, 39, 1981-1990; Balzarini, J., et
al., Proc. National Acad Sci USA, 1996, 93, 7295-7299; Siddiqui, A.
Q., et al., J. Med. Chem., 1999, 42, 4122-4128; Eisenberg, E. J.,
et al., Nucleosides, Nucleotides and Nucleic Acids, 2001, 20,
1091-1098; Lee, W. A., et al., Antimicrobial Agents and
Chemotherapy, 2005, 49, 1898); US 2006/0241064; and WO
2007/095269.
[0017] Also limiting the utility of nucleosides as viable
therapeutic agents is their sometimes poor physicochemical and
pharmacokinetic properties. These poor properties can limit the
intestinal absorption of an agent and limit uptake into the target
tissue or cell. To improve on their properties prodrugs of
nucleosides have been employed. It has been demonstrated that
preparation of nucleoside phosphoramidates improves the systemic
absorption of a nucleoside and furthermore, the phosphoramidate
moiety of these "pronucleotides" is masked with neutral lipophilic
groups to obtain a suitable partition coefficient to optimize
uptake and transport into the cell dramatically enhancing the
intracellular concentration of the nucleoside monophosphate analog
relative to administering the parent nucleoside alone.
Enzyme-mediated hydrolysis of the phosphate ester moiety produces a
nucleoside monophosphate wherein the rate limiting initial
phosphorylation is unnecessary.
SUMMARY OF THE INVENTION
[0018] The present invention is directed toward novel
phosphoramidate prodrugs of nucleoside derivatives for the
treatment of viral infections in mammals, which is a compound, its
stereoisomers, salts (acid or basic addition salts), hydrates,
solvates, or crystalline forms thereof, represented by the
following structure:
##STR00002## [0019] wherein
[0020] (a) R.sup.1 is hydrogen, n-alkyl; branched alkyl;
cycloalkyl; or aryl, which includes, but is not limited to, phenyl
or naphthyl, where phenyl or naphthyl are optionally substituted
with at least one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C.sub.1-6
haloalkyl, --N(R.sup.1').sub.2, C.sub.1-6 acylamino,
--NHSO.sub.2C.sub.1-6 alkyl, --SO.sub.2N(R.sup.1').sub.2,
COR.sup.1'', and --SO.sub.2C.sub.1-6 alkyl; (R.sup.1' is
independently hydrogen or alkyl, which includes, but is not limited
to, C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl,
R.sup.1'' is --OR' or --N(R.sup.1').sub.2);
[0021] (b) R.sup.2 is hydrogen, C.sub.1-10 alkyl, R.sup.3a or
R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so as to form a
cyclic ring that includes the adjoining N and C atoms,
C(O)CR.sup.3aR.sup.3bNHR.sup.1, where n is 2 to 4 and R.sup.1,
R.sup.3a, and R.sup.3b;
[0022] (c) R.sup.3a and R.sup.3b are (i) independently selected
from hydrogen, C.sub.1-10 alkyl, cycloalkyl,
--(CH.sub.2).sub.c(NR.sup.3').sub.2, C.sub.1-6 hydroxyalkyl,
--CH.sub.2SH, --(CH.sub.2).sub.2S(O).sub.dMe,
--(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, (1H-indol-3-yl)methyl,
(1H-imidazol-4-yl)methyl, --(CH.sub.2).sub.eCOR.sup.3'', aryl and
aryl C.sub.1-3 alkyl, said aryl groups optionally substituted with
a group selected from hydroxyl, C.sub.1-10 alkyl, C.sub.1-6 alkoxy,
halogen, nitro and cyano; (ii) R.sup.3a and R.sup.3b both are
C.sub.1-6 alkyl; (iii) R.sup.3a and R.sup.3b together are
(CH.sub.2).sub.f so as to form a spiro ring; (iv) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 2 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
--CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H, where R.sup.3' is independently
hydrogen or alkyl, which includes, but is not limited to,
C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl, R.sup.3''
is OR' or --N(R.sup.3').sub.2);
[0023] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy, di(lower
alkyl)-amino, or halogen, C.sub.1-10 haloalkyl, C.sub.3-10
cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl,
such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl,
or substituted heteroaryl;
[0024] (e) R.sup.5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl),
hydroxyl lower alkyl, i.e., --(CH.sub.2).sub.pOH, where p is 1-6,
including hydroxyl methyl (CH.sub.2OH), CH.sub.2F, N.sub.3,
CH.sub.2CN, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, alkyne (optionally substituted), or
halogen, including F, Cl, Br, or I, with the provisos that when X
is OH, base is cytosine and R.sup.6 is H, R.sup.5 cannot be N.sub.3
and when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F and B is a
purine base, R.sup.5 cannot be H;
[0025] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0026] (g) X is H, OH, F, OMe, halogen, NH.sub.2, or N.sub.3;
[0027] (h) Y is OH, H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, vinyl, N.sub.3, CN, Cl, Br, F, I, NO.sub.2,
OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.2-4
alkynyl), OC(O)O(C.sub.2-4 alkenyl), OC.sub.1-10 haloalkyl,
O(aminoacyl), O(C.sub.1-10 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4
alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4
alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4
alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-18 acyl).sub.2, wherein alkyl,
alkynyl, alkenyl and vinyl are optionally substituted by N.sub.3,
CN, one to three halogen (Cl, Br, F, I), NO.sub.2, C(O)O(C.sub.1-4
alkyl), C(O)O(C.sub.1-4 alkyl), C(O)O(C.sub.2-4 alkynyl),
C(O)O(C.sub.2-4 alkenyl), O(C.sub.1-4 acyl), O(C.sub.1-4 alkyl),
O(C.sub.2-4 alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl),
S(C.sub.2-4 alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl),
SO(C.sub.1-4 alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-4 acyl).sub.2;
[0028] the base is a naturally occurring or modified purine or
pyrimidine base represented by the following structures:
##STR00003## [0029] wherein
[0030] Z is N or CR.sup.12;
[0031] R.sup.7, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are
independently H, F, Cl, Br, I, OH, OR', SH, SR', NH.sub.2, NHR',
NR'.sub.2, lower alkyl of C.sub.1-C.sub.6, halogenated (F, Cl, Br,
I) lower alkyl of C.sub.1-C.sub.6, lower alkenyl of
C.sub.2-C.sub.6, halogenated (F, Cl, Br, I) lower alkenyl of
C.sub.2-C.sub.6, lower alkynyl of C.sub.2-C.sub.6 such as
C.ident.CH, halogenated (F, Cl, Br, I) lower alkynyl of
C.sub.2-C.sub.6, lower alkoxy of C.sub.1-C.sub.6, halogenated (F,
Cl, Br, I) lower alkoxy of C.sub.1-C.sub.6, CO.sub.2H, CO.sub.2R',
CONH.sub.2, CONHR', CONR'.sub.2, CH.dbd.CHCO.sub.2H, or
CH.dbd.CHCO.sub.2R',
[0032] wherein R' is an optionally substituted alkyl, which
includes, but is not limited to, an optionally substituted
C.sub.1-20 alkyl, an optionally substituted C.sub.1-10 alkyl, an
optionally substituted lower alkyl; an optionally substituted
cycloalkyl; an optionally substituted alkynyl of C.sub.2-C.sub.6,
an optionally substituted lower alkenyl of C.sub.2-C.sub.6, or
optionally substituted acyl, which includes but is not limited to
C(O) alkyl, C(O)(C.sub.1-20 alkyl), C(O)(C.sub.1-10 alkyl), or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0033] R.sup.12 is H, halogen (including F, Cl, Br, I), OH, OR',
SH, SR', NH.sub.2, NHR', NR'.sub.2, NO.sub.2 lower alkyl of
C.sub.1-C.sub.6, halogenated (F, Cl, Br, I) lower alkyl of
C.sub.1-C.sub.6, lower alkenyl of C.sub.2-C.sub.6, halogenated (F,
Cl, Br, I) lower alkenyl of C.sub.2-C.sub.6, lower alkynyl of
C.sub.2-C.sub.6, halogenated (F, Cl, Br, I) lower alkynyl of
C.sub.2-C.sub.6, lower alkoxy of C.sub.1-C.sub.6, halogenated (F,
Cl, Br, I) lower alkoxy of C.sub.1-C.sub.6, CO.sub.2H, CO.sub.2R',
CONH.sub.2, CONHR', CONR'.sub.2, CH.dbd.CHCO.sub.2H, or
CH.dbd.CHCO.sub.2R'; with the proviso that when base is represented
by the structure c with R.sup.11 being hydrogen, R.sup.12 is not a:
(i) --C.ident.C--H, (ii) --C.dbd.CH.sub.2, or (iii) --NO.sub.2.
Definitions
[0034] The phrase "a" or "an" entity as used herein refers to one
or more of that entity; for example, a compound refers to one or
more compounds or at least one compound. As such, the terms "a" (or
"an"), "one or more", and "at least one" can be used
interchangeably herein.
[0035] The phrase "as defined herein above" refers to the first
definition provided in the Summary of the Invention.
[0036] The terms "optional" or "optionally" as used herein means
that a subsequently described event or circumstance may but need
not occur, and that the description includes instances where the
event or circumstance occurs and instances in which it does not.
For example, "optional bond" means that the bond may or may not be
present, and that the description includes single, double, or
triple bonds.
[0037] The term "independently" is used herein to indicate that a
variable is applied in any one instance without regard to the
presence or absence of a variable having that same or a different
definition within the same compound. Thus, in a compound in which R
appears twice and is defined as "independently carbon or nitrogen",
both R's can be carbon, both R's can be nitrogen, or one R' can be
carbon and the other nitrogen.
[0038] The term "alkenyl" refers to an unsubstituted hydrocarbon
chain radical having from 2 to 10 carbon atoms having one or two
olefinic double bonds, preferably one olefinic double bond. The
term "C.sub.2-N alkenyl" refers to an alkenyl comprising 2 to N
carbon atoms, where N is an integer having the following values: 3,
4, 5, 6, 7, 8, 9, or 10. The term "C.sub.2-10 alkenyl" refers to an
alkenyl comprising 2 to 10 carbon atoms. The term "C.sub.2-4
alkenyl" refers to an alkenyl comprising 2 to 4 carbon atoms.
Examples include, but are not limited to, vinyl, 1-propenyl,
2-propenyl (allyl) or 2-butenyl (crotyl).
[0039] The term "halogenated alkenyl" refers to an alkenyl
comprising at least one of F, Cl, Br, and I.
[0040] The term "alkyl" refers to an unbranched or branched chain,
saturated, monovalent hydrocarbon residue containing 1 to 30 carbon
atoms. The term "C.sub.1-M alkyl" refers to an alkyl comprising 1
to M carbon atoms, where M is an integer having the following
values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. The term
"C.sub.1-4 alkyl" refers to an alkyl containing 1 to 4 carbon
atoms. The term "lower alkyl" denotes a straight or branched chain
hydrocarbon residue comprising 1 to 6 carbon atoms. "C.sub.1-20
alkyl" as used herein refers to an alkyl comprising 1 to 20 carbon
atoms. "C.sub.1-10 alkyl" as used herein refers to an alkyl
comprising 1 to 10 carbons. Examples of alkyl groups include, but
are not limited to, lower alkyl groups include methyl, ethyl,
propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl,
neopentyl, hexyl, heptyl, and octyl. The term (ar)alkyl or
(heteroaryl)alkyl indicate the alkyl group is optionally
substituted by an aryl or a heteroaryl group respectively.
[0041] The term "cycloalkyl" refers to an unsubstituted or
substituted carbocycle, in which the carbocycle contains 3 to 10
carbon atoms; preferably 3 to 8 carbon atoms; more preferably 3 to
6 carbon atoms (i.e., lower cycloalkyls). Examples of cycloalkyl
groups include, but are not limited to, cyclopropyl,
2-methyl-cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0042] The term "cycloalkyl alkyl" refers to an additionally
unsubstituted or substituted alkyl substituted by a lower
cycloalkyl. Examples of cycloalkyl alkyls include, but are not
limited to, any one of methyl, ethyl, propyl, i-propyl, n-butyl,
i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl,
and octyl that is substituted with cyclopropyl,
2-methyl-cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0043] The term "cycloheteroalkyl" refers to an unsubstituted or
substituted heterocycle, in which the heterocycle contains 2 to 9
carbon atoms; preferably 2 to 7 carbon atoms; more preferably 2 to
5 carbon atoms. Examples of cycloheteroalkyls include, but are not
limited to, aziridin-2-yl, N--C.sub.1-3-alkyl-aziridin-2-yl,
azetidinyl, N--C.sub.1-3-alkyl-azetidin-m'-yl, pyrrolidin-m'-yl,
N--C.sub.1-3-alkyl-pyrrolidin-m'-yl, piperidin-m'-yl, and
N--C.sub.1-3-alkyl-piperidin-m'-yl, where m' is 2, 3, or 4
depending on the cycloheteroalkyl. Specific examples of
N--C.sub.1-3-alkyl-cycloheteroalkyls include, but are not limited
to, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,
N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,
N-methyl-piperidin-2-yl, N-methyl-piperidin-3-yl, and
N-methyl-piperidin-4-yl. In the instance of R.sup.4, the point of
attachment between the cycloheteroalkyl ring carbon and the oxygen
occurs at any one of m'
[0044] The term "heterocycle" refers to an unsubstituted or
substituted heterocycle containing carbon, hydrogen, and at least
one of N, O, and S, where the C and N can be trivalent or
tetravalent, i.e., sp.sup.2- or sp.sup.3-hybridized. Examples of
heterocycles include, but are not limited to, aziridine, azetidine,
pyrrolidine, piperidine, imidazole, oxazole, piperazine, etc. In
the instance of piperazine, as related to R.sup.10 for NR'.sub.2,
the corresponding opposite nitrogen atom of the piperazinyl is
substituted by a lower alkyl represented by the following
structure:
##STR00004##
Preferably, the opposite nitrogen of the piperazinyl is substituted
by a methyl group.
[0045] The term "halogenated alkyl" (or "haloalkyl") refers to an
unbranched or branched chain alkyl comprising at least one of F,
Cl, Br, and I. The term "C.sub.1-M haloalkyl" refers to an alkyl
comprising 1 to M carbon atoms that comprises at least one of F,
Cl, Br, and I, where M is an integer having the following values:
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. "C.sub.1-3 haloalkyl"
refers to a haloalkyl comprising 1 to 3 carbons and at least one of
F, Cl, Br, and I. The term "halogenated lower alkyl" (or "lower
haloalkyl") refers to a haloalkyl comprising 1 to 6 carbon atoms
and at least one of F, Cl, Br, and I. Examples include, but are not
limited to, fluoromethyl, chloromethyl, bromomethyl, iodomethyl,
difluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl,
trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl,
1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl,
2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl,
2,2-difluoroethyl, 2,2-dichloroethyl, 2,2-dibromomethyl,
2-2-diiodomethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl,
2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl.
[0046] The term "alkynyl" refers to an unbranched or branched
hydrocarbon chain radical having from 2 to 10 carbon atoms,
preferably 2 to 5 carbon atoms, and having one triple bond. The
term "C.sub.2-N alkynyl" refers to an alkynyl comprising 2 to N
carbon atoms, where N is an integer having the following values: 3,
4, 5, 6, 7, 8, 9, or 10. The term "C C.sub.2-4 alkynyl" refers to
an alkynyl comprising 2 to 4 carbon atoms. The term "C.sub.2-10
alkynyl" refers to an alkynyl comprising 2 to 10 carbons. Examples
include, but are limited to, ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 2-butynyl or 3-butynyl.
[0047] The term "halogenated alkynyl" refers to an unbranched or
branched hydrocarbon chain radical having from 2 to 10 carbon
atoms, preferably 2 to 5 carbon atoms, and having one triple bond
and at least one of F, Cl, Br, and I.
[0048] The term "cycloalkyl" refers to a saturated carbocyclic ring
comprising 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The term
"C.sub.3-7 cycloalkyl" as used herein refers to a cycloalkyl
comprising 3 to 7 carbons in the carbocyclic ring.
[0049] The term "alkoxy" refers to an --O-alkyl group or an
--O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined
above. Examples of --O-alkyl groups include, but are not limited
to, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy,
i-butyloxy, t-butyloxy. "Lower alkoxy" as used herein denotes an
alkoxy group with a "lower alkyl" group as previously defined.
"C.sub.1-10 alkoxy" refers to an --O-alkyl wherein alkyl is
C.sub.1-10. Examples of --O-cycloalkyl groups include, but are not
limited to, --O-c-propyl, --O-c-butyl, --O-c-pentyl, and
--O-c-hexyl.
[0050] The term "halogenated alkoxy" refers to an --O-alkyl group
in which the alkyl group comprises at least one of F, Cl, Br, and
I.
[0051] The term "halogenated lower alkoxy" refers to an --O-(lower
alkyl) group in which the lower alkyl group comprises at least one
of F, Cl, Br, and I.
[0052] The term "amino acid" includes naturally occurring and
synthetic .alpha., .beta. .gamma. or .delta. amino acids, and
includes but is not limited to, amino acids found in proteins, i.e.
glycine, alanine, valine, leucine, isoleucine, methionine,
phenylalanine, tryptophan, proline, serine, threonine, cysteine,
tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,
arginine and histidine. In a preferred embodiment, the amino acid
is in the L-configuration. Alternatively, the amino acid can be a
derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl,
phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl,
threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl,
aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl,
.beta.-alanyl, .beta.-valinyl, .beta.-leucinyl, .beta.-isoleucinyl,
.beta.-prolinyl, .beta.-phenylalaninyl, .beta.-tryptophanyl,
.beta.-methioninyl, .beta.-glycinyl, .beta.-serinyl,
.beta.-threoninyl, .beta.-cysteinyl, .beta.-tyrosinyl,
.beta.-asparaginyl, .beta.-glutaminyl, .beta.-aspartoyl,
.beta.-glutaroyl, .beta.-lysinyl, .beta.-argininyl or
.beta.-histidinyl. When the term amino acid is used, it is
considered to be a specific and independent disclosure of each of
the esters of .alpha., .beta. .gamma. or .delta. glycine, alanine,
valine, leucine, isoleucine, methionine, phenylalanine, tryptophan,
proline, serine, threonine, cysteine, tyrosine, asparagine,
glutamine, aspartate, glutamate, lysine, arginine and histidine in
the D and L-configurations.
[0053] The term "aminoacyl" includes N,N-unsubstituted,
N,N-monosubstituted, and N,N-disubstituted derivatives of naturally
occurring and synthetic .alpha., .beta. .gamma. or .delta. amino
acyls, where the amino acyls are derived from amino acids. The
amino-nitrogen can be substituted or unsubstituted. When the
amino-nitrogen is substituted, the nitrogen is either mono- or
di-substituted, where the substituent bound to the amino-nitrogen
is a lower alkyl or an alkaryl. In the instance of its use for Y,
the expression "O(aminoacyl)" is used. It is understood that the
C3' carbon of the ribose is bound to the oxygen "O", which is then
bound to the carbonyl carbon of the aminoacyl.
[0054] The terms "alkylamino" or "arylamino" refer to an amino
group that has one or two alkyl or aryl substituents,
respectively.
[0055] The term "protected," as used herein and unless otherwise
defined, refers to a group that is added to an oxygen, nitrogen, or
phosphorus atom to prevent its further reaction or for other
purposes. A wide variety of oxygen and nitrogen protecting groups
are known to those skilled in the art of organic synthesis.
Non-limiting examples include: C(O)-alkyl, C(O)Ph, C(O)aryl,
CH.sub.3, CH.sub.2-alkyl, CH.sub.2-alkenyl, CH.sub.2Ph,
CH.sub.2-aryl, CH.sub.2O-alkyl, CH.sub.2O-aryl, SO.sub.2-alkyl,
SO.sub.2-aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,
and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).
[0056] The term "aryl," as used herein, and unless otherwise
specified, refers to substituted or unsubstituted phenyl (Ph),
biphenyl, or naphthyl, preferably the term aryl refers to
substituted or unsubstituted phenyl. The aryl group can be
substituted with one or more moieties selected from among hydroxyl,
F, Cl, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro,
cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and
phosphonate, either unprotected, or protected as necessary, as
known to those skilled in the art, for example, as taught in T.W.
Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis,"
3rd ed., John Wiley & Sons, 1999.
[0057] The terms "alkaryl" or "alkylaryl" refer to an alkyl group
with an aryl substituent, such as benzyl. The terms "aralkyl" or
"arylalkyl" refer to an aryl group with an alkyl substituent.
[0058] The term "di(lower alkyl)amino-lower alkyl" refers to a
lower alkyl substituted by an amino group that is itself
substituted by two lower alkyl groups. Examples include, but are
not limited to, (CH.sub.3).sub.2NCH.sub.2,
(CH.sub.3).sub.2NCH.sub.2CH.sub.2,
(CH.sub.3).sub.2NCH.sub.2CH.sub.2CH.sub.2, etc. The examples above
show lower alkyls substituted at the terminus carbon atom with an
N,N-dimethyl-amino substituent. These are intended as examples only
and are not intended to limit the meaning of the term "di(lower
alkyl)amino-lower alkyl" so as to require the same. It is
contemplated that the lower alkyl chain can be substituted with an
N,N-di(lower alkyl)-amino at any point along the chain, e.g.,
CH.sub.3CH(N-(lower alkyl).sub.2)CH.sub.2CH.sub.2.
[0059] The term "halo," as used herein, includes chloro, bromo,
iodo and fluoro.
[0060] The term "acyl" refers to a substituent containing a
carbonyl moiety and a non-carbonyl moiety. The carbonyl moiety
contains a double-bond between the carbonyl carbon and a
heteroatom, where the heteroatom is selected from among O, N and S.
When the heteroatom is N, the N is substituted by a lower alkyl.
The non-carbonyl moiety is selected from straight, branched, and
cyclic alkyl, which includes, but is not limited to, a straight,
branched, or cyclic C.sub.1-20 alkyl, C.sub.1-10 alkyl, or lower
alkyl; alkoxyalkyl, including methoxymethyl; aralkyl, including
benzyl; aryloxyalkyl, such as phenoxymethyl; or aryl, including
phenyl optionally substituted with halogen (F, Cl, Br, I),
hydroxyl, C.sub.1 to C.sub.4 alkyl, or C.sub.1 to C.sub.4 alkoxy,
sulfonate esters, such as alkyl or aralkyl sulphonyl, including
methanesulfonyl, the mono, di or triphosphate ester, trityl or
monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g.
dimethyl-t-butylsilyl) or diphenylmethylsilyl. When at least one
aryl group is present in the non-carbonyl moiety, it is preferred
that the aryl group comprises a phenyl group.
[0061] The term "lower acyl" refers to an acyl group in which the
non-carbonyl moiety is lower alkyl.
[0062] The term "purine" or "pyrimidine" base includes, but is not
limited to, adenine, N.sup.6-alkylpurines, N.sup.6-acylpurines
(wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl),
N.sup.6-benzylpurine, N.sup.6-halopurine, N.sup.6-vinylpurine,
N.sup.6-acetylenic purine, N.sup.6-acyl purine,
N.sup.6-hydroxyalkyl purine, N.sup.6-allcylaminopurine,
N.sup.6-thioallcyl purine, N.sup.2-alkylpurines,
N.sup.2-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine,
5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2-
and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including
5-fluorouracil, C.sup.5-alkylpyrimidines,
C.sup.5-benzylpyrimidines, C.sup.5-halopyrimidines,
C.sup.5-vinylpyrimidine, C.sup.5-acetylenic pyrimidine,
C.sup.5-acyl pyrimidine, C.sup.5-hydroxyalkyl purine,
C.sup.5-amidopyrimidine, C.sup.5-cyanopyrimidine,
C.sup.5-iodopyrimidine, C.sup.6-lodo-pyrimidine, C.sup.5--Br-vinyl
pyrimidine, C.sup.6--Br-vinyl pyrimidine, C.sup.5-nitropyrimidine,
C.sup.5-amino-pyrimidine, N.sup.2-alkylpurines,
N.sup.2-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl,
triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and
pyrazolopyrimidinyl. Purine bases include, but are not limited to,
guanine, adenine, hypoxanthine, 2,6-diaminopurine, and
6-chloropurine. Functional oxygen and nitrogen groups on the base
can be protected as necessary or desired. Suitable protecting
groups are well known to those skilled in the art, and include
trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and
t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as
acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
[0063] The term "tautomerism" and "tautomers" have their accepted
plain meanings.
[0064] The term "P*" means that the phosphorous atom is chiral and
that it has a corresponding Cahn-Ingold-Prelog designation of "R"
or "S" which have their accepted plain meanings. It is contemplated
that compounds of the formula I are racemic because the chirality
at phosphorous. Applicants contemplate use of the racemate and/or
the resolved enantiomers. In some instances, an asterisk does not
appear next to the phosphoroamidate phosphorous atom. In these
instances, it is understood that the phosphorous atom is chiral and
that one of ordinary skill understands this to be so unless the
substituents bound to the phosphorous exclude the possibility of
chirality at phosphorous, such as in P(O)Cl.sub.3.
DETAILED DESCRIPTION OF THE INVENTION
[0065] An aspect of the invention is directed to a compound, its
salts, hydrates, solvates, crystalline forms, and the like
represented by formula I:
##STR00005## [0066] wherein
[0067] (a) R.sup.1 is hydrogen, n-alkyl; branched alkyl;
cycloalkyl; or aryl, which includes, but is not limited to, phenyl
or naphthyl, where phenyl or naphthyl are optionally substituted
with at least one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C.sub.1-6
haloalkyl, --N(R.sup.1').sub.2, C.sub.1-6 acylamino,
--NHSO.sub.2C.sub.1-6 alkyl, --SO.sub.2N(R.sup.1').sub.2,
COR.sup.1'', and --SO.sub.2C.sub.1-6 alkyl; (R.sup.1' is
independently hydrogen or alkyl, which includes, but is not limited
to, C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl,
R.sup.1'' is --OR' or --N(R.sup.1').sub.2);
[0068] (b) R.sup.2 is hydrogen, C.sub.1-10 alkyl, R.sup.3a or
R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so as to form a
cyclic ring that includes the adjoining N and C atoms,
C(O)CR.sup.3aR.sup.3bNHR.sup.1, where n is 2 to 4 and R.sup.1,
R.sup.3a, and R.sup.3b;
[0069] (c) R.sup.3a and R.sup.3b are (i) independently selected
from hydrogen, C.sub.1-10 alkyl, cycloalkyl,
--(CH.sub.2).sub.c(NR.sup.3').sub.2, C.sub.1-6 hydroxyalkyl,
--CH.sub.2SH, --(CH.sub.2).sub.2S(O).sub.dMe,
--(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, (1H-indol-3-yl)methyl,
(1H-imidazol-4-yl)methyl, --(CH.sub.2).sub.eCOR.sup.3'', aryl and
aryl C.sub.1-3 alkyl, said aryl groups optionally substituted with
a group selected from hydroxyl, C.sub.1-10 alkyl, C.sub.1-6 alkoxy,
halogen, nitro and cyano; (ii) R.sup.3a and R.sup.3b both are
C.sub.1-6 alkyl; (iii) R.sup.3a and R.sup.3b together are
(CH.sub.2).sub.f so as to form a spiro ring; (iv) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 2 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
--CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H, where R.sup.3' is independently
hydrogen or alkyl, which includes, but is not limited to,
C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl, R.sup.3''
is --OR' or --N(R.sup.3').sub.2);
[0070] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy, di(lower
alkyl)-amino, or halogen, C.sub.1-10 haloalkyl, C.sub.3-10
cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl,
such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl,
or substituted heteroaryl;
[0071] (e) R.sup.5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl),
hydroxyl lower alkyl, i.e., --(CH.sub.2).sub.pOH, where p is 1-6,
including hydroxyl methyl (CH.sub.2OH), CH.sub.2F, N.sub.3,
CH.sub.2CN, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, alkyne (optionally substituted), or
halogen, including F, Cl, Br, or I, with the provisos that when X
is OH, base is cytosine and R.sup.6 is H, R.sup.5 cannot be N.sub.3
and when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F and B is a
purine base, R.sup.5 cannot be H;
[0072] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0073] (g) X is H, OH, F, OMe, halogen, NH.sub.2, or N.sub.3;
[0074] (h) Y is OH, H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, vinyl, N.sub.3, CN, Cl, Br, F, I, NO.sub.2,
OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.2-4
alkynyl), OC(O)O(C.sub.2-4 alkenyl), OC.sub.1-10 haloalkyl,
O(aminoacyl), O(C.sub.1-10 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4
alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4
alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4
alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-18 acyl).sub.2, wherein alkyl,
alkynyl, alkenyl and vinyl are optionally substituted by N.sub.3,
CN, one to three halogen (Cl, Br, F, I), NO.sub.2, C(O)O(C.sub.1-4
alkyl), C(O)O(C.sub.1-4 alkyl), C(O)O(C.sub.2-4 alkynyl),
C(O)O(C.sub.2-4 alkenyl), O(C.sub.1-4 acyl), O(C.sub.1-4 alkyl),
O(C.sub.2-4 alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl),
S(C.sub.2-4 alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl),
SO(C.sub.1-4 alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-4 acyl).sub.2;
[0075] the base is a naturally occurring or modified purine or
pyrimidine base represented by the following structures:
##STR00006## [0076] wherein
[0077] Z is N or CR.sup.12;
[0078] R.sup.7, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are
independently H, F, Cl, Br, I, OH, OR', SH, SR', NH.sub.2, NHR',
NR'.sub.2, lower alkyl of C.sub.1-C.sub.6, halogenated (F, Cl, Br,
I) lower alkyl of C.sub.1-C.sub.6, lower alkenyl of
C.sub.2-C.sub.6, halogenated (F, Cl, Br, I) lower alkenyl of
C.sub.2-C.sub.6, lower alkynyl of C.sub.2-C.sub.6 such as
C.ident.CH, halogenated (F, Cl, Br, I) lower alkynyl of
C.sub.2-C.sub.6, lower alkoxy of C.sub.1-C.sub.6, halogenated (F,
Cl, Br, I) lower alkoxy of C.sub.1-C.sub.6, CO.sub.2H, CO.sub.2R',
CONH.sub.2, CONHR', CONR'.sub.2, CH.dbd.CHCO.sub.2H, or
CH.dbd.CHCO.sub.2R',
[0079] wherein R' is an optionally substituted alkyl, which
includes, but is not limited to, an optionally substituted
C.sub.1-20 alkyl, an optionally substituted C.sub.1-10 alkyl, an
optionally substituted lower alkyl; an optionally substituted
cycloalkyl; an optionally substituted alkynyl of C.sub.2-C.sub.6,
an optionally substituted lower alkenyl of C.sub.2-C.sub.6, or
optionally substituted acyl, which includes but is not limited to
C(O) alkyl, C(O)(C.sub.1-20 alkyl), C(O)(C.sub.1-10 alkyl), or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0080] R.sup.12 is H, halogen (including F, Cl, Br, I), OH, OR',
SH, SR', NH.sub.2, NHR', NR'.sub.2, NO.sub.2 lower alkyl of
C.sub.1-C.sub.6, halogenated (F, Cl, Br, I) lower alkyl of
C.sub.1-C.sub.6, lower alkenyl of C.sub.2-C.sub.6, halogenated (F,
Cl, Br, I) lower alkenyl of C.sub.2-C.sub.6, lower alkynyl of
C.sub.2-C.sub.6, halogenated (F, Cl, Br, I) lower alkynyl of
C.sub.2-C.sub.6, lower alkoxy of C.sub.1-C.sub.6, halogenated (F,
Cl, Br, I) lower alkoxy of C.sub.1-C.sub.6, CO.sub.2H, CO.sub.2R',
CONH.sub.2, CONHR', CONR'.sub.2, CH.dbd.CHCO.sub.2H, or
CH.dbd.CHCO.sub.2R; with the proviso that when base is represented
by the structure c with R.sup.11 being hydrogen, R.sup.12 is not a:
(i) --C.ident.C--H, (ii) --C.dbd.CH.sub.2, or (iii) --NO.sub.2.
[0081] As can be appreciated from the structure represented by
formula I above, there are myriad ways to express the several
embodiments and aspects of each embodiment of the present
invention. As seen below, the inventors have disclosed certain
embodiments directed to the compound of formula I, each having
several aspects, based on the identity of the modified purine or
pyrimidine base. This is not intended to be an explicit or implicit
admission that the three embodiments are independent or distinct
nor should it be interpreted as such. Rather, it is intended to
convey information so that the full breadth of the present
invention can be understood. Furthermore, the following
embodiments, and aspects thereof, are not meant to be limiting on
the full breadth of the invention as recited by the structure of
formula I.
[0082] A first embodiment of the invention is directed to a
compound represented by formula I-1:
##STR00007##
[0083] wherein
[0084] (a) R.sup.1 is hydrogen, n-alkyl; branched alkyl;
cycloalkyl; or aryl, which includes, but is not limited to, phenyl
or naphthyl, where phenyl or naphthyl are optionally substituted
with at least one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C.sub.1-6
haloalkyl, --N(R.sup.1').sub.2, C.sub.1-6 acylamino,
--NHSO.sub.2C.sub.1-6 alkyl, --SO.sub.2N(R.sup.1').sub.2,
COR.sup.1'', and --SO.sub.2C.sub.1-6 alkyl; (R.sup.1' is
independently hydrogen or alkyl, which includes, but is not limited
to, C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl,
R.sup.1'' is --OR' or --N(R.sup.1').sub.2);
[0085] (b) R.sup.2 is hydrogen, C.sub.1-10 alkyl, R.sup.3a or
R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so as to form a
cyclic ring that includes the adjoining N and C atoms,
C(O)CR.sup.3aR.sup.3bNHR.sup.1, where n is 2 to 4 and R.sup.1,
R.sup.3a, and R.sup.3b;
[0086] (c) R.sup.3a and R.sup.3b are (i) independently selected
from hydrogen, C.sub.1-10 alkyl, cycloalkyl,
--(CH.sub.2).sub.c(NR.sup.3').sub.2, C.sub.1-6 hydroxyalkyl,
--CH.sub.2SH, --(CH.sub.2).sub.2S(O).sub.dMe,
--(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, (1H-indol-3-yl)methyl,
(1H-imidazol-4-yl)methyl, --(CH.sub.2).sub.eCOR.sup.3'', aryl and
aryl C.sub.1-3 alkyl, said aryl groups optionally substituted with
a group selected from hydroxyl, C.sub.1-10 alkyl, C.sub.1-6 alkoxy,
halogen, nitro and cyano; (ii) R.sup.3a and R.sup.3b both are
C.sub.1-6 alkyl; (iii) R.sup.3a and R.sup.3b together are
(CH.sub.2).sub.f so as to form a spiro ring; (iv) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 2 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
--CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H, where R.sup.3' is independently
hydrogen or alkyl, which includes, but is not limited to,
C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl, R.sup.3''
is --OR' or --N(R.sup.3').sub.2);
[0087] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy, di(lower
alkyl)-amino, or halogen, C.sub.1-10 haloalkyl, C.sub.3-10
cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(lower
alkyl)-amino, aryl, such as phenyl, heteroaryl, such as, pyridinyl,
substituted aryl, or substituted heteroaryl;
[0088] (e) R.sup.5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl),
hydroxyl lower alkyl, i.e., --(CH.sub.2).sub.pOH, where p is 1-6,
including hydroxyl methyl (CH.sub.2OH), CH.sub.2F, N.sub.3,
CH.sub.2CN, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, alkyne (optionally substituted), or
halogen, including F, Cl, Br, or I, with the provisos that when X
is OH, base is cytosine and R.sup.6 is H, R.sup.5 cannot be N.sub.3
and when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F and B is a
purine base, R.sup.5 cannot be H;
[0089] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0090] (g) X is H, OH, F, OMe, Cl, Br, I, NH.sub.2, or N.sub.3;
[0091] (h) Y is OH, H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, vinyl, N.sub.3, CN, Cl, Br, F, I, NO.sub.2,
OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.2-4
alkynyl), OC(O)O(C.sub.2-4 alkenyl), OC.sub.1-10 haloalkyl,
O(aminoacyl), O(C.sub.1-10 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4
alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4
alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4
alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-18 acyl).sub.2, wherein alkyl,
alkynyl, alkenyl and vinyl are optionally substituted by N.sub.3,
CN, one to three halogen (Cl, Br, F, I), NO.sub.2, C(O)O(C.sub.1-4
alkyl), C(O)O(C.sub.1-4 alkyl), C(O)O(C.sub.2-4 alkynyl),
C(O)O(C.sub.2-4 alkenyl), O(C.sub.1-4 acyl), O(C.sub.1-4 alkyl),
O(C.sub.2-4 alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl),
S(C.sub.2-4 alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl),
SO(C.sub.1-4 alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-4 acyl).sub.2;
[0092] (i) R.sup.7, R.sup.8, R.sup.9 are independently H, F, Cl,
Br, I, OH, OR', SH, SR', NH.sub.2, NHR', NR'.sub.2, lower alkyl,
halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl of
C.sub.2-C.sub.6, CO.sub.2H, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, wherein R' is a C.sub.1-20 alkyl; a C.sub.1-20
cycloalkyl; a C.sub.2-C.sub.6 alkenyl, a C.sub.2-C.sub.6
alkynyl.
[0093] A first aspect of the first embodiment is directed to a
compound represented by formula I-1
[0094] wherein
[0095] (a) R.sup.1 is hydrogen, n-alkyl or aryl, which includes,
but is not limited to, phenyl or naphthyl, where phenyl or naphthyl
are optionally substituted with at least one of C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C.sub.1-6
haloalkyl;
[0096] (b) R.sup.2 is hydrogen or CH.sub.3;
[0097] (c) R.sup.3a and R.sup.3b are independently (i) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 3 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), or CH.sub.2SH and
R.sup.3b is H;
[0098] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy, di(lower
alkyl)-amino, or halogen, C.sub.1-10 haloalkyl, C.sub.3-10
cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl,
such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl,
or substituted heteroaryl;
[0099] (e) R.sup.5 is H, CN, CH.sub.3, vinyl, OCH.sub.3,
OCH.sub.2CH.sub.3, CH.sub.2OH, CH.sub.2(halo), such as CH.sub.2F,
N.sub.3, CH.sub.2CN, CH.sub.2N.sub.3, CH.sub.2NH.sub.2,
CH.sub.2NHCH.sub.3, CH.sub.2N(CH.sub.3).sub.2, halogen, including
F, Cl, Br, or I, with the provisos that when X is OH, base is
cytosine and R.sup.6 is H, R.sup.5 cannot be N.sub.3;
[0100] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0101] (g) X is H, OH, F, OMe, Cl, Br, I, NH.sub.2, or N.sub.3;
[0102] (h) Y is OH, H, C.sub.1-4 alkyl, vinyl, N.sub.3, CN, Cl, Br,
F, I, O(C.sub.1-6 acyl), O(C.sub.1-4 alkyl), NH.sub.2, NH(C.sub.1-4
alkyl), NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4
acyl), N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-18 acyl).sub.2, wherein
alkyl, alkynyl, alkenyl and vinyl are optionally substituted by
N.sub.3, CN, one to three halogen (Cl, Br, F, I), NO.sub.2,
OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.2-4
alkynyl), OC(O)O(C.sub.2-4 alkenyl), OC.sub.1-4 haloalkyl,
O(aminoacyl), O(C.sub.1-4 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4
alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4
alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4
alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2 (C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, or N(C.sub.1-4 acyl).sub.2;
[0103] (i) R.sup.7, R.sup.8, R.sup.9 are independently H, F, Cl,
Br, I, OH, OR', SH, SR', NH.sub.2, NHR', NR'.sub.2, lower alkyl,
halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl of
C.sub.2-C.sub.6, CO.sub.2H, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, wherein R' is a C.sub.1-20 alkyl; a C.sub.1-20
cycloalkyl; a C.sub.2-C.sub.6 alkenyl, a C.sub.2-C.sub.6
alkynyl.
[0104] A second aspect of the first embodiment is directed to a
compound represented by formula I-1
[0105] wherein
[0106] (a) R.sup.1 is hydrogen, n-alkyl or a substituted or
unsubstituted phenyl, where the substitutent of the substituted
phenyl is at least one of a C.sub.1-3 alkyl, a C.sub.1-3 alkoxy, F,
Cl, Br, I, nitro, cyano, and a C.sub.1-3 haloalkyl;
[0107] (b) R.sup.2 is hydrogen or CH.sub.3;
[0108] (c) R.sup.3a and R.sup.3b are independently (i) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 3 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), or CH.sub.2SH and
R.sup.3b is H;
[0109] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
di(lower alkyl)amino-lower alkyl, or aminoacyl;
[0110] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2(halo), such as CH.sub.2F, N.sub.3, CH.sub.2CN,
CH.sub.2N.sub.3, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, halogen, including F, Cl, Br, or I, with
the provisos that when X is OH, base is cytosine and R.sup.6 is H,
R.sup.5 cannot be N.sub.3;
[0111] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0112] (g) X is H, OH, F, OCH.sub.3, NH.sub.2, or N.sub.3;
[0113] (h) Y is OH, H, CH.sub.3, vinyl, N.sub.3, CN, Cl, Br, F, I,
OC(O)CH.sub.3, OCH.sub.3, NH.sub.2, NHCH.sub.3, NH(vinyl),
NH(acetyl), NH(C(O)CH.sub.3), N(CH.sub.3).sub.2,
N(C(O)CH.sub.3).sub.2, or O(aminoacyl);
[0114] (i) R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I,
OH, OCH.sub.3, SH, SCH.sub.3, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl,
Br, or I and q is 1 to 3, vinyl, CO.sub.2H, CO.sub.2CH.sub.3,
CONH.sub.2, CONHCH.sub.3, or CON(CH.sub.3).sub.2; and
[0115] (j) R.sup.9 is selected from among OH, OCH.sub.3, SH,
SCH.sub.3, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, OC(O)(C1-20
alkyl), which include but are not limited to
OC(O)(CH.sub.2),CH.sub.3, NHC(O)(C1-20 alkyl), which include but
are not limited to NHC(O)(CH.sub.2).sub.sCH.sub.3, and
N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, which include but is not
limited to N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, where s is an
integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, and 19.
[0116] A third aspect of the first embodiment is directed to a
compound represented by formula I-1
[0117] wherein
[0118] (a) R.sup.1 is hydrogen, n-alkyl or a substituted or
unsubstituted phenyl, where the substitutent of the substituted
phenyl is at least one of a CH.sub.3, OCH.sub.3, F, Cl, Br, I,
nitro, cyano, and a CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I,
and q is 1-3;
[0119] (b) R.sup.2 is hydrogen or CH.sub.3;
[0120] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl or R.sup.3a is CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H;
[0121] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, lower haloalkyl, di(lower
alkyl)amino-lower alkyl, or aminoacyl;
[0122] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2(halo), such as CH.sub.2F, N.sub.3, CH.sub.2CN,
CH.sub.2N.sub.3, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, halogen, including F, Cl, Br, or I, with
the provisos that when X is OH, base is cytosine and R.sup.6 is H,
R.sup.5 cannot be N.sub.3;
[0123] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0124] (g) X is H, OH, F, OCH.sub.3, NH.sub.2, or N.sub.3;
[0125] (h) Y is OH, H, CH.sub.3, vinyl, N.sub.3, CN, Cl, Br, F, I,
OC(O)CH.sub.3, OCH.sub.3, NH.sub.2, NHCH.sub.3, NH(vinyl),
NH(acetyl), NH(C(O)CH.sub.3), N(CH.sub.3).sub.2,
N(C(O)CH.sub.3).sub.2, or O(aminoacyl);
[0126] (i) R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I,
OH, OCH.sub.3, SH, SCH.sub.3, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl,
Br, or I and q is 1 to 3, vinyl, CO.sub.2H, CO.sub.2CH.sub.3,
CONH.sub.2, CONHCH.sub.3, or CON(CH.sub.3).sub.2, wherein R' is a
C.sub.1-20 alkyl; a C.sub.1-20 cycloalkyl; a C.sub.2-C.sub.6
alkenyl, a C.sub.2-C.sub.6 alkynyl; and
[0127] (j) R.sup.9 is selected from among OH, OCH.sub.3, SH,
SCH.sub.3, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, OC(O)(C1-20
alkyl), which include but are not limited to
OC(O)(CH.sub.2),CH.sub.3, NHC(O)(C1-20 alkyl), which include but
are not limited to NHC(O)(CH.sub.2),CH.sub.3, and
N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, which include but is not
limited to N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, where s is an
integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, and 19.
[0128] A fourth aspect of the first embodiment is directed to a
compound represented by formula I-2
##STR00008##
[0129] wherein
[0130] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
or a substituted or unsubstituted phenyl, where the substitutent of
the substituted phenyl is at least one of a CH.sub.3, OCH.sub.3, F,
Cl, Br, I, nitro, cyano, and a CH.sub.3-qX.sub.q, where X is F, Cl,
Br, or I, and q is 1-3;
[0131] (b) R.sup.2 is hydrogen or CH.sub.3;
[0132] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl or R.sup.3a is CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H;
[0133] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy or halogen,
C.sub.1-10 haloalkyl, C.sub.3-10 cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl,
aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted
aryl, or substituted heteroaryl;
[0134] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, N.sub.3, CH.sub.2CN, CH.sub.2N.sub.3, CH.sub.2NH.sub.2,
CH.sub.2NHCH.sub.3, CH.sub.2N(CH.sub.3).sub.2, halogen, including
F, Cl, Br, or I, with the provisos that when X is OH, base is
cytosine and R.sup.6 is H, R.sup.5 cannot be N.sub.3;
[0135] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0136] (g) X is H, OH, F, OCH.sub.3, Cl, Br, I, NH.sub.2, or
N.sub.3;
[0137] (h) Y is OH, H, CH.sub.3, vinyl, N.sub.3, CN, Cl, Br, F, I,
OC(O)CH.sub.3, OCH.sub.3, NH.sub.2, NHCH.sub.3, NH(vinyl),
NH(acetyl), NH(C(O)CH.sub.3), N(CH.sub.3).sub.2,
N(C(O)CH.sub.3).sub.2, or O(aminoacyl);
[0138] (i) R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I,
OH, OCH.sub.3, SH, SCH.sub.3, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl,
Br, or I and q is 1 to 3, vinyl, CO.sub.2H, CO.sub.2CH.sub.3,
CONH.sub.2, CONHCH.sub.3, or CON(CH.sub.3).sub.2, wherein R' is a
C.sub.1-20 alkyl; a C.sub.1-20 cycloalkyl; a C.sub.2-C.sub.6
alkenyl, a C.sub.2-C.sub.6 alkynyl; and
[0139] (j) R.sup.9 is selected from among OH, OCH.sub.3, SH,
SCH.sub.3, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, OC(O)(C1-20
alkyl), which include but are not limited to
OC(O)(CH.sub.2),CH.sub.3, NHC(O)(C1-20 alkyl), which include but
are not limited to NHC(O)(CH.sub.2),CH.sub.3, and
N(C(O)(CH.sub.2).sub.sCH.sub.3, which include but is not limited to
N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, where s is an integer
selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, and 19.
[0140] A fifth aspect of the first embodiment is directed to a
compound represented by formula I-2
[0141] wherein
[0142] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0143] (b) R.sup.2 is hydrogen or CH.sub.3;
[0144] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl;
[0145] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, lower haloalkyl, di(lower
alkyl)amino-lower alkyl, or aminoacyl;
[0146] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, halogen, including F, Cl, Br, or I;
[0147] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0148] (g) X is H, OH, F, OCH.sub.3, NH.sub.2, or N.sub.3;
[0149] (h) Y is OH, H, CH.sub.3, vinyl, N.sub.3, CN, Cl, Br, F, I,
OC(O)CH.sub.3, OCH.sub.3, or O(aminoacyl);
[0150] (i) R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I,
OH, OCH.sub.3, SH, SCH.sub.3, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl,
Br, or I and q is 1 to 3, vinyl, CO.sub.2H, CO.sub.2CH.sub.3,
CONH.sub.2, CONHCH.sub.3, or CON(CH.sub.3).sub.2, wherein R' is a
C.sub.1-20 alkyl; a C.sub.1-20 cycloalkyl; a C.sub.2-C.sub.6
alkenyl, a C.sub.2-C.sub.6 alkynyl; and
[0151] (j) R.sup.9 is selected from among OH, OCH.sub.3, SH,
SCH.sub.3, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2,
OC(O)(C.sub.1-20 alkyl), which include but are not limited to
OC(O)(CH.sub.2).sub.sCH.sub.3, NHC(O)(C.sub.1-20 alkyl), which
include but are not limited to NHC(O)(CH.sub.2).sub.sCH.sub.3, and
N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, which include but is not
limited to N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, where s is an
integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, and 19.
[0152] A sixth aspect of the first embodiment is directed to a
compound represented by formula I-2
[0153] wherein
[0154] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0155] (b) R.sup.2 is hydrogen or CH.sub.3;
[0156] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0157] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy or halogen,
C.sub.1-10 haloalkyl, C.sub.3-10 cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl,
aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted
aryl, or substituted heteroaryl;
[0158] (e) R.sup.5 is H, OMe, CN, CH.sub.2F, F, Cl, Br, or I;
[0159] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0160] (g) X is H, OH, F, OCH.sub.3, F, Cl, Br, I, or N.sub.3;
[0161] (h) Y is H, OH, CH.sub.3, F, Cl, Br, I, or N.sub.3,
OCH.sub.3, OC(O)CH.sub.3, or O(aminoacyl);
[0162] (i) R.sup.7 and R.sup.8 are independently H, F, Br,
SCH.sub.3, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I
and q is 1 to 3, vinyl, CO.sub.2CH.sub.3, CONH.sub.2, CONHCH.sub.3,
or CON(CH.sub.3).sub.2; and
[0163] (j) R.sup.9 is selected from among OH, OCH.sub.3, SH,
SCH.sub.3, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2,
OC(O)(C.sub.1-20 alkyl), which include but are not limited to
OC(O)(CH.sub.2).sub.sCH.sub.3, NHC(O)(C.sub.1-20 alkyl), which
include but are not limited to NHC(O)(CH.sub.2).sub.sCH.sub.3, and
N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, which include but is not
limited to N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, where s is an
integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, and 19.
[0164] A seventh aspect of the first embodiment is directed to a
compound represented by formula I-2
[0165] wherein
[0166] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0167] (b) R.sup.2 is hydrogen;
[0168] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0169] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0170] (e) R.sup.5 is H;
[0171] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0172] (g) X is H, OH, OCH.sub.3, F, or N.sub.3;
[0173] (h) Y is OH, OCH.sub.3, OC(O)CH.sub.3, or O(aminoacyl);
[0174] (i) R.sup.7 and R.sup.8 are independently H, F, Br,
SCH.sub.3, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I
and q is 1 to 3, vinyl, CO.sub.2CH.sub.3, CONH.sub.2, CONHCH.sub.3,
or CON(CH.sub.3).sub.2; and
[0175] (j) R.sup.9 is selected from among OH, OCH.sub.3, NH.sub.2,
NHCH.sub.3, N(CH.sub.3).sub.2, OC(O)(C.sub.1-20 alkyl), which
include but are not limited to OC(O)(CH.sub.2),CH.sub.3,
NHC(O)(C.sub.1-20 alkyl), which include but are not limited to
NHC(O)(CH.sub.2),CH.sub.3, and
N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, which include but is not
limited to N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, where s is an
integer selected from among 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, and 19.
[0176] An eighth aspect of the first embodiment is directed to a
compound represented by formula I-2
[0177] wherein
[0178] (a) R.sup.1 is hydrogen, methyl, phenyl, p-bromo-phenyl,
p-chloro-phenyl, p-fluorophenyl;
[0179] (b) R.sup.2 is hydrogen;
[0180] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0181] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0182] (e) R.sup.5 is H;
[0183] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0184] (g) X is H, OH, OCH.sub.3, F, or N.sub.3;
[0185] (h) Y is OH, OCH.sub.3, OC(O)CH.sub.3, or O(aminoacyl);
[0186] (i) R.sup.7 and R.sup.8 are independently H, F, Br,
SCH.sub.3, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I
and q is 1 to 3, vinyl, CO.sub.2CH.sub.3, CONH.sub.2, CONHCH.sub.3,
or CON(CH.sub.3).sub.2;
[0187] (j) R.sup.9 is selected from among OH, OCH.sub.3, NH.sub.2,
NHCH.sub.3, N(CH.sub.3).sub.2, OC(O)(C.sub.1-20 alkyl), which
include but are not limited to OC(O)(CH.sub.2),CH.sub.3,
NHC(O)(C.sub.1-20 alkyl), which include but are not limited to
NHC(O)(CH.sub.2),CH.sub.3, and
N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, which include but is not
limited to N(C(O)(CH.sub.2).sub.sCH.sub.3).sub.2, where s is an
integer selected from among 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, and 19.
[0188] A second embodiment of the invention is directed to a
compound represented by formula I in which the base is a structure
represented by formula b above, wherein R.sup.1, R.sup.2, R.sup.3a,
R.sup.3b, R.sup.4, R.sup.5, R.sup.6, X, Y, R.sup.7, and R.sup.8 are
defined in the Summary of the Invention section above.
[0189] A first aspect of the second embodiment is directed to a
compound represented by formula I-3
##STR00009##
[0190] wherein
[0191] (a) R.sup.1 is hydrogen, n-alkyl; branched alkyl;
cycloalkyl; or aryl, which includes, but is not limited to, phenyl
or naphthyl, where phenyl or naphthyl are optionally substituted
with at least one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C.sub.1-6
haloalkyl, --N(R.sup.1').sub.2, C.sub.1-6 acylamino,
--NHSO.sub.2C.sub.1-6 alkyl, --SO.sub.2N(R.sup.1').sub.2,
COR.sup.1'', and --SO.sub.2C.sub.1-6 alkyl; (R.sup.1' is
independently hydrogen or alkyl, which includes, but is not limited
to, C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl,
R.sup.1'' is --OR' or --N(R.sup.1').sub.2);
[0192] (b) R.sup.2 is hydrogen or CH.sub.3;
[0193] (c) R.sup.3a and R.sup.3b are (i) independently selected
from hydrogen, C.sub.1-10 alkyl, cycloalkyl,
--(CH.sub.2).sub.c(NR.sup.3').sub.2, C.sub.1-6 hydroxyalkyl,
--CH.sub.2SH, --(CH.sub.2).sub.2S(O).sub.dMe,
--(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, (1H-indol-3-yl)methyl,
(1H-imidazol-4-yl)methyl, --(CH.sub.2).sub.eCOR.sup.3'', aryl and
aryl C.sub.1-3 alkyl, said aryl groups optionally substituted with
a group selected from hydroxyl, C.sub.1-10 alkyl, C.sub.1-6 alkoxy,
halogen, nitro and cyano; (ii) R.sup.3a and R.sup.3b both are
C.sub.1-6 alkyl; (iii) R.sup.3a and R.sup.3b together are
(CH.sub.2).sub.f so as to form a spiro ring; (iv) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 2 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
--CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H, where R.sup.3' is independently
hydrogen or alkyl, which includes, but is not limited to,
C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl, R.sup.3''
is --OR' or --N(R.sup.3').sub.2);
[0194] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy or halogen,
C.sub.1-10 haloalkyl, C.sub.3-10 cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl,
aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted
aryl, or substituted heteroaryl;
[0195] (e) R.sup.5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl),
hydroxyl lower alkyl, i.e., --(CH.sub.2).sub.pOH, where p is 1-6,
including hydroxyl methyl (CH.sub.2OH), CH.sub.2F, N.sub.3,
CH.sub.2CN, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, alkyne (optionally substituted), or
halogen, including F, Cl, Br, or I, with the provisos that when X
is OH, base is cytosine and R.sup.6 is H, R.sup.5 cannot be N.sub.3
and when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F and B is a
purine base, R.sup.5 cannot be H;
[0196] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0197] (g) X is H, OH, F, OMe, Cl, Br, I, NH.sub.2, or N.sub.3;
[0198] (h) Y is OH, H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, vinyl, N.sub.3, CN, Cl, Br, F, I, NO.sub.2,
OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.2-4
alkynyl), OC(O)O(C.sub.2-4 alkenyl), OC.sub.1-10 haloalkyl,
O(aminoacyl), O(C.sub.1-10 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4
alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4
alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4
alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, or N(C.sub.1-18 acyl).sub.2, wherein
alkyl, alkynyl, alkenyl and vinyl are optionally substituted by
N.sub.3, CN, one to three halogen (Cl, Br, F, I), NO.sub.2,
C(O)O(C.sub.1-4 alkyl), C(O)O(C.sub.1-4 alkyl), C(O)O(C.sub.2-4
alkynyl), C(O)O(C.sub.2-4 alkenyl), O(C.sub.1-4 acyl), O(C.sub.1-4
alkyl), O(C.sub.2-4 alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4
alkyl), S(C.sub.2-4 alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4
acyl), SO(C.sub.1-4 alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4
alkenyl), SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, or N(C.sub.1-4 acyl).sub.2;
[0199] (i) R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I,
OH, OR', SH, SR', NH.sub.2, NHR', NR'.sub.2, lower alkyl,
halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl of
C.sub.2-C.sub.6, CO.sub.2H, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, wherein R' is a C.sub.1-20 alkyl; a C.sub.1-20
cycloalkyl; a C.sub.2-C.sub.6 alkenyl, a C.sub.2-C.sub.6
alkynyl.
[0200] The second aspect of the second embodiment is directed to a
compound represented by formula I-3
[0201] wherein
[0202] (a) R.sup.1 is hydrogen, n-alkyl or aryl, which includes,
but is not limited to, phenyl or naphthyl, where phenyl or naphthyl
are optionally substituted with at least one of C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C.sub.1-6
haloalkyl;
[0203] (b) R.sup.2 is hydrogen or CH.sub.3;
[0204] (c) R.sup.3a and R.sup.3b are independently (i) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 3 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), or CH.sub.2SH and
R.sup.3b is H;
[0205] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy or halogen,
C.sub.1-10 haloalkyl, C.sub.3-10 cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl,
aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted
aryl, or substituted heteroaryl;
[0206] (e) R.sup.5 is H, CN, CH.sub.3, vinyl, OCH.sub.3,
OCH.sub.2CH.sub.3, CH.sub.2OH, CH.sub.2(halo), such as CH.sub.2F,
N.sub.3, CH.sub.2CN, CH.sub.2N.sub.3, CH.sub.2NH.sub.2,
CH.sub.2NHCH.sub.3, CH.sub.2N(CH.sub.3).sub.2, halogen, including
F, Cl, Br, or I;
[0207] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0208] (g) X is H, OH, F, OMe, halogen, NH.sub.2, or N.sub.3;
[0209] (h) Y is OH, H, C.sub.1-4 alkyl, vinyl, N.sub.3, CN, Cl, Br,
F, I, O(C.sub.1-6 acyl), O(C.sub.1-4 alkyl), NH.sub.2, NH(C.sub.1-4
alkyl), NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4
acyl), N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-18 acyl).sub.2, wherein
alkyl, alkynyl, alkenyl and vinyl are optionally substituted by
N.sub.3, CN, one to three halogen (Cl, Br, F, I), NO.sub.2,
OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.2-4
alkynyl), OC(O)O(C.sub.2-4 alkenyl), OC.sub.1-10 haloalkyl,
O(aminoacyl), O(C.sub.1-4 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4
alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4
alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4
alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-4 acyl).sub.2;
[0210] (i) R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I,
OH, OR', SH, SR', NH.sub.2, NHR', NR'.sub.2, lower alkyl,
halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl of
C.sub.2-C.sub.6, CO.sub.2H, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, wherein R' is a C.sub.1-20 alkyl; a C.sub.1-20
cycloalkyl; a C.sub.2-C.sub.6 alkenyl, a C.sub.2-C.sub.6
alkynyl.
[0211] The third aspect of the second embodiment is directed to a
compound represented by formula I-3
[0212] wherein
[0213] (a) R.sup.1 is hydrogen, n-alkyl or a substituted or
unsubstituted phenyl, where the substitutent of the substituted
phenyl is at least one of a C.sub.1-3 alkyl, a C.sub.1-3 alkoxy, F,
Cl, Br, I, nitro, cyano, and a C.sub.1-3 haloalkyl;
[0214] (b) R.sup.2 is hydrogen, CH.sub.3, R.sup.3a or R.sup.3b and
R.sup.2 together are (CH.sub.2).sub.3 so as to form a cyclic ring
that includes the adjoining N and C atoms,
C(O)CR.sup.3aR.sup.3bNHR.sup.1, where n is 2 to 4 and R.sup.1,
R.sup.3a, and R.sup.3b are as defined herein;
[0215] (c) R.sup.3a and R.sup.3b are independently (i) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 3 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H;
[0216] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0217] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2(halo), such as CH.sub.2F, N.sub.3, CH.sub.2CN,
CH.sub.2N.sub.3, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, halogen, including F, Cl, Br, or I;
[0218] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0219] (g) X is H, OH, F, OCH.sub.3, halogen, NH.sub.2, or
N.sub.3
[0220] (h) Y is OH, H, CH.sub.3, vinyl, N.sub.3, CN, Cl, Br, F, I,
OC(O)CH.sub.3, OCH.sub.3, NH.sub.2, NHCH.sub.3, NH(vinyl),
NH(acetyl), NH(C(O)CH.sub.3), N(CH.sub.3).sub.2,
N(C(O)CH.sub.3).sub.2;
[0221] (i) R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I,
OH, OCH.sub.3, SH, SCH.sub.3, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl,
Br, or I and q is 1 to 3, vinyl, CO.sub.2H, CO.sub.2CH.sub.3,
CONH.sub.2, CONHCH.sub.3, or CON(CH.sub.3).sub.2.
[0222] The fourth aspect of the second embodiment is directed to a
compound represented by formula I-3
[0223] wherein
[0224] (a) R.sup.1 is hydrogen, n-alkyl or a substituted or
unsubstituted phenyl, where the substitutent of the substituted
phenyl is at least one of a CH.sub.3, OCH.sub.3, F, Cl, Br, I,
nitro, cyano, and a CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I,
and q is 1-3;
[0225] (b) R.sup.2 is hydrogen or CH.sub.3;
[0226] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl or R.sup.3a is CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H;
[0227] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0228] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2(halo), such as CH.sub.2F, N.sub.3, CH.sub.2CN,
CH.sub.2N.sub.3, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, halogen, including F, Cl, Br, or I;
[0229] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0230] (g) X is H, OH, F, OCH.sub.3, NH.sub.2, or N.sub.3;
[0231] (h) Y is OH, H, CH.sub.3, vinyl, N.sub.3, CN, Cl, Br, F, I,
OC(O)CH.sub.3, OCH.sub.3, NH.sub.2, NHCH.sub.3, NH(vinyl),
NH(acetyl), NH(C(O)CH.sub.3), N(CH.sub.3).sub.2,
N(C(O)CH.sub.3).sub.2;
[0232] (i) R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I,
OH, OCH.sub.3, SH, SCH.sub.3, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl,
Br, or I and q is 1 to 3, vinyl, CO.sub.2H, CO.sub.2CH.sub.3,
CONH.sub.2, CONHCH.sub.3, or CON(CH.sub.3).sub.2, wherein R' is a
C.sub.1-20 alkyl; a C.sub.1-20 cycloalkyl; a C.sub.2-C.sub.6
alkenyl, a C.sub.2-C.sub.6 alkynyl.
[0233] The fifth aspect of the second embodiment is directed to a
compound represented by formula I-4
##STR00010##
[0234] wherein
[0235] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
or a substituted or unsubstituted phenyl, where the substitutent of
the substituted phenyl is at least one of a CH.sub.3, OCH.sub.3, F,
Cl, Br, I, nitro, cyano, and a CH.sub.3-qX.sub.q, where X is F, Cl,
Br, or I, and q is 1-3;
[0236] (b) R.sup.2 is hydrogen or CH.sub.3;
[0237] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl or R.sup.3a is CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H;
[0238] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0239] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, N.sub.3, CH.sub.2CN, CH.sub.2N.sub.3, CH.sub.2NH.sub.2,
CH.sub.2NHCH.sub.3, CH.sub.2N(CH.sub.3).sub.2, halogen, including
F, Cl, Br, or I;
[0240] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0241] (g) X is H, OH, F, OCH.sub.3, Cl, Br, I, NH.sub.2, or
N.sub.3;
[0242] (h) Y is OH, H, CH.sub.3, vinyl, N.sub.3, CN, Cl, Br, F, I,
OC(O)CH.sub.3, OCH.sub.3, NH.sub.2, NHCH.sub.3, NH(vinyl),
NH(acetyl), NH(C(O)CH.sub.3), N(CH.sub.3).sub.2,
N(C(O)CH.sub.3).sub.2;
[0243] (i) R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I,
OH, OCH.sub.3, SH, SCH.sub.3, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl,
Br, or I and q is 1 to 3, vinyl, CO.sub.2H, CO.sub.2CH.sub.3,
CONH.sub.2, CONHCH.sub.3, or CON(CH.sub.3).sub.2, wherein R' is a
C.sub.1-20 alkyl; a C.sub.1-20 cycloalkyl; a C.sub.2-C.sub.6
alkenyl, a C.sub.2-C.sub.6 alkynyl,
[0244] The sixth aspect of the second embodiment is directed to a
compound represented by formula I-4
[0245] wherein
[0246] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0247] (b) R.sup.2 is hydrogen or CH.sub.3;
[0248] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl;
[0249] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0250] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, halogen, including F, Cl, Br, or I;
[0251] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0252] (g) X is H, OH, F, OCH.sub.3, NH.sub.2, or N.sub.3;
[0253] (h) Y is OH, H, CH.sub.3, vinyl, NH.sub.2, N.sub.3, CN, Cl,
Br, F, I, OC(O)CH.sub.3, OCH.sub.3;
[0254] (i) R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I,
OH, OCH.sub.3, SH, SCH.sub.3, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl,
Br, or I and q is 1 to 3, vinyl, CO.sub.2H, CO.sub.2CH.sub.3,
CONH.sub.2, CONHCH.sub.3, or CON(CH.sub.3).sub.2, wherein R' is a
C.sub.1-20 alkyl; a C.sub.1-20 cycloalkyl; a C.sub.2-C.sub.6
alkenyl, a C.sub.2-C.sub.6 alkynyl.
[0255] The seventh aspect of the second embodiment is directed to a
compound represented by formula I-4
[0256] wherein
[0257] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0258] (b) R.sup.2 is hydrogen or CH.sub.3;
[0259] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0260] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0261] (e) R.sup.5 is H, OMe, CN, CH.sub.2F, F, Cl, Br, or I;
[0262] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0263] (g) X is H, OH, F, OCH.sub.3, F, Cl, Br, I, NH.sub.2 or
N.sub.3;
[0264] (h) Y is H, OH, CH.sub.3, F, Cl, Br, I, NH.sub.2 or N.sub.3,
OCH3, or OC(O)CH.sub.3;
[0265] (i) R.sup.7 and R.sup.8 are independently H, F, Br,
SCH.sub.3, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I
and q is 1 to 3, vinyl, CO.sub.2CH.sub.3, CONH.sub.2, CONHCH.sub.3,
or CON(CH.sub.3).sub.2;
[0266] The eighth aspect of the second embodiment is directed to a
compound represented by formula I-4
[0267] wherein
[0268] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0269] (b) R.sup.2 is hydrogen;
[0270] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0271] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0272] (e) R.sup.5 is H;
[0273] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0274] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0275] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0276] (i) R.sup.7 and R.sup.8 are independently H, F, Br,
SCH.sub.3, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I
and q is 1 to 3, vinyl, CO.sub.2CH.sub.3, CONH.sub.2, CONHCH.sub.3,
or CON(CH.sub.3).sub.2.
[0277] The ninth aspect of the second embodiment is directed to a
compound represented by formula I-4
[0278] wherein
[0279] (a) R.sup.1 is hydrogen, methyl, phenyl, p-bromo-phenyl,
p-chloro-phenyl, p-fluorophenyl;
[0280] (b) R.sup.2 is hydrogen;
[0281] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0282] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0283] (e) R.sup.5 is H;
[0284] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0285] (g) X is H, OH, OCH.sub.3, F, or N.sub.3;
[0286] (h) Y is OH, OCH.sub.3, or OC(O)CH.sub.3;
[0287] (i) R.sup.7 and R.sup.8 are independently H, F, Br,
SCH.sub.3, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I
and q is 1 to 3, vinyl, CO.sub.2CH.sub.3, CONH.sub.2, CONHCH.sub.3,
or CON(CH.sub.3).sub.2.
[0288] A third embodiment of the invention is directed to a
compound represented by formula I in which the base is a structure
represented by formula c above, wherein R.sup.1, R.sup.2, R.sup.3a,
R.sup.3b, R.sup.4, R.sup.5, R.sup.6, X, Y, Z, R.sup.10, R.sup.11,
and R.sup.12 are defined in the Summary of the Invention section
above; with the proviso that R.sup.11 is not H.
[0289] A first aspect of the third embodiment is directed to a
compound represented by formula I-5
##STR00011##
[0290] wherein
[0291] (a) R.sup.1 is hydrogen, n-alkyl; branched alkyl;
cycloalkyl; or aryl, which includes, but is not limited to, phenyl
or naphthyl, where phenyl or naphthyl are optionally substituted
with at least one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C.sub.1-6
haloalkyl, --N(R.sup.1').sub.2, C.sub.1-6 acylamino,
--NHSO.sub.2C.sub.1-6 alkyl, --SO.sub.2N(R.sup.1').sub.2,
COR.sup.1'', and --SO.sub.2C.sub.1-6 alkyl; (R.sup.1' is
independently hydrogen or alkyl, which includes, but is not limited
to, C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl,
R.sup.1'' is --OR' or --N(R.sup.1').sub.2);
[0292] (b) R.sup.2 is hydrogen or CH.sub.3;
[0293] (c) R.sup.3a and R.sup.3b are (i) independently selected
from hydrogen, C.sub.1-10 alkyl, cycloalkyl,
--(CH.sub.2).sub.c(NR.sup.3').sub.2, C.sub.1-6 hydroxyalkyl,
--CH.sub.2SH, --(CH.sub.2).sub.2S(O).sub.dMe,
--(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, (1H-indol-3-yl)methyl,
(1H-imidazol-4-yl)methyl, --(CH.sub.2).sub.eCOR.sup.3, aryl and
aryl C.sub.1-3 alkyl, said aryl groups optionally substituted with
a group selected from hydroxyl, C.sub.1-10 alkyl, C.sub.1-6 alkoxy,
halogen, nitro and cyano; (ii) R.sup.3a and R.sup.3b both are
C.sub.1-6 alkyl; (iii) R.sup.3a and R.sup.3b together are
(CH.sub.2).sub.f so as to form a spiro ring; (iv) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 2 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is from H,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
--CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H, where R.sup.3' is independently
hydrogen or alkyl, which includes, but is not limited to,
C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl, R.sup.3''
is --OR' or --N(R.sup.3').sub.2);
[0294] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy or halogen,
C.sub.1-10 haloalkyl, C.sub.3-10 cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl,
aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted
aryl, or substituted heteroaryl;
[0295] (e) R.sup.5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl),
hydroxyl lower alkyl, i.e., --(CH.sub.2).sub.pOH, where p is 1-6,
including hydroxyl methyl (CH.sub.2OH), CH.sub.2F, N.sub.3,
CH.sub.2CN, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, alkyne (optionally substituted), or
halogen, including F, Cl, Br, or I, with the provisos that when X
is OH, base is cytosine and R.sup.6 is H, R.sup.5 cannot be N.sub.3
and when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F and B is a
purine base, R.sup.5 cannot be H;
[0296] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0297] (g) X is H, OH, F, OMe, halogen, NH.sub.2, or N.sub.3;
[0298] (h) Y is OH, H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, vinyl, N.sub.3, CN, Cl, Br, F, I, NO.sub.2,
OC(O)O(C.sub.1-4alkyl), OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.2-4
alkynyl), OC(O)O(C.sub.2-4 alkenyl), OC.sub.1-10 haloalkyl,
O(aminoacyl), O(C.sub.1-10 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4
alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4
alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4
alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl), SO.sub.2
(C.sub.1-4 acyl), SO.sub.2 (C.sub.1-4 alkyl), SO.sub.2 (C.sub.2-4
alkynyl), SO.sub.2(C.sub.2-4 alkenyl), OS(O).sub.2(C.sub.1-4 acyl),
OS(O).sub.2(C.sub.1-4 alkyl), OS(O).sub.2(C.sub.2-4 alkenyl),
NH.sub.2, NH(C.sub.1-4 alkyl), NH(C.sub.2-4 alkenyl), NH(C.sub.2-4
alkynyl), NH(C.sub.1-4 acyl), N(C.sub.1-4 alkyl).sub.2,
N(C.sub.1-18 acyl).sub.2, wherein alkyl, alkynyl, alkenyl and vinyl
are optionally substituted by N.sub.3, CN, one to three halogen
(Cl, Br, F, I), NO.sub.2, C(O)O(C.sub.1-4 alkyl), C(O)O(C.sub.1-4
alkyl), C(O)O(C.sub.2-4 alkynyl), C(O)O(C.sub.2-4 alkenyl),
O(C.sub.1-4 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4 alkenyl),
S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4 alkynyl),
S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4 alkyl),
SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl), SO.sub.2(C.sub.1-4
acyl), SO.sub.2(C.sub.1-4 alkyl), SO.sub.2(C.sub.2-4 alkynyl),
SO.sub.2(C.sub.2-4 alkenyl), OS(O).sub.2(C.sub.1-4 acyl),
OS(O).sub.2(C.sub.1-4 alkyl), OS(O).sub.2(C.sub.2-4 alkenyl),
NH.sub.2, NH(C.sub.1-4 alkyl), NH(C.sub.2-4 alkenyl), NH(C.sub.2-4
alkynyl), NH(C.sub.1-4 acyl), N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-4
acyl).sub.2;
[0299] (i) R.sup.10 and R.sup.11 are independently H, F, Cl, Br, I,
OH, OR', SH, SR', NH.sub.2, NHR', NR'.sub.2, lower alkyl of
C.sub.1-C.sub.6, halogenated (F, Cl, Br, I) lower alkyl of
C.sub.1-C.sub.6, lower alkenyl of C.sub.2-C.sub.6, halogenated (F,
Cl, Br, I) lower alkenyl of C.sub.2-C.sub.6, lower alkynyl of
C.sub.2-C.sub.6 such as C.ident.CH, halogenated (F, Cl, Br, I)
lower alkynyl of C.sub.2-C.sub.6, lower alkoxy of C.sub.1-C.sub.6,
halogenated (F, Cl, Br, I) lower alkoxy of C.sub.1-C.sub.6,
CO.sub.2H, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R', with the proviso that
when R.sup.10 is OH and R.sup.11 is not NH.sub.2;
[0300] wherein R' is an optionally substituted alkyl, which
includes, but is not limited to, an optionally substituted
C.sub.1-20 alkyl, an optionally substituted C.sub.1-10 alkyl, an
optionally substituted lower alkyl; an optionally substituted
cycloalkyl; an optionally substituted alkynyl of C.sub.2-C.sub.6,
an optionally substituted lower alkenyl of C.sub.2-C.sub.6, or
optionally substituted acyl, which includes but is not limited to
C(O) alkyl, C(O)(C.sub.1-20 alkyl), C(O)(C.sub.1-10 alkyl), or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0301] (j) Z is N or CR.sup.12; and
[0302] R.sup.12 is an H, halogen (including F, Cl, Br, I), OH, OR',
SH, SR', NH.sub.2, NHR', NR'.sub.2, NO.sub.2 lower alkyl of
C.sub.1-C.sub.6, halogenated (F, Cl, Br, I) lower alkyl of
C.sub.1-C.sub.6, lower alkenyl of C.sub.2-C.sub.6, halogenated (F,
Cl, Br, I) lower alkenyl of C.sub.2-C.sub.6, lower alkynyl of
C.sub.2-C.sub.6, halogenated (F, Cl, Br, I) lower alkynyl of
C.sub.2-C.sub.6, lower alkoxy of C.sub.1-C.sub.6, halogenated (F,
Cl, Br, I) lower alkoxy of C.sub.1-C.sub.6, CO.sub.2H, CO.sub.2R',
CONH.sub.2, CONHR', CONR'.sub.2, CH.dbd.CHCO.sub.2H, or
CH.dbd.CHCO.sub.2R'.
[0303] A second aspect of the third embodiment is directed to a
compound represented by formula I-5
[0304] wherein
[0305] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0306] (b) R.sup.2 is hydrogen or CH.sub.3;
[0307] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl;
[0308] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, lower haloalkyl, or di(lower
alkyl)amino-lower alkyl;
[0309] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, halogen, including F, Cl, Br, or I, with the provisos
that when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot
be H.
[0310] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0311] (g) X is H, OH, F, OCH.sub.3, Cl, Br, I, NH.sub.2, or
N.sub.3;
[0312] (h) Y is OH, H, CH.sub.3, vinyl, NH.sub.2, N.sub.3, CN, Cl,
Br, F, I, OC(O)CH.sub.3, OCH.sub.3;
[0313] (i) R.sup.10 and R.sup.11 are independently H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R', with the
proviso that when R.sup.10 is OH and R.sup.11 is not NH.sub.2;
[0314] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0315] (j) Z is N or CR.sup.12; and
[0316] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0317] A third aspect of the third embodiment is directed to a
compound represented by formula I-5
[0318] wherein
[0319] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0320] (b) R.sup.2 is hydrogen or CH.sub.3;
[0321] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0322] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0323] (e) R.sup.5 is H, CN, CH.sub.2F, F, Cl, Br, or I; with the
proviso that X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5
cannot be H;
[0324] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0325] (g) X is H, OH, F, OCH.sub.3, F, Cl, Br, I, NH.sub.2 or
N.sub.3;
[0326] (h) Y is H, OH, CH.sub.3, F, Cl, Br, I, NH.sub.2 or N.sub.3,
OCH.sub.3, or OC(O)CH.sub.3;
[0327] (i) R.sup.10 and R.sup.11 are independently H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R', with the
proviso that when R.sup.10 is OH and R.sup.11 is not NH.sub.2;
[0328] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0329] (j) Z is N or CR.sup.12; and
[0330] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0331] A fourth aspect of the third embodiment is directed to a
compound represented by formula I-5
[0332] wherein
[0333] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0334] (b) R.sup.2 is hydrogen;
[0335] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0336] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0337] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0338] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0339] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0340] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0341] (i) R.sup.10 and R.sup.11 are independently H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R', with the
proviso that when R.sup.10 is OH and R.sup.11 is not NH.sub.2;
[0342] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0343] (j) Z is N or CR.sup.12; and
[0344] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0345] A fifth aspect of the third embodiment is directed to a
compound represented by formula I-5
[0346] wherein
[0347] (a) R.sup.1 is hydrogen, methyl, phenyl, p-bromo-phenyl,
p-chloro-phenyl, p-fluorophenyl;
[0348] (b) R.sup.2 is hydrogen;
[0349] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0350] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0351] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0352] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0353] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0354] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0355] (i) R.sup.10 and R.sup.11 are independently H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R', with the
proviso that when R.sup.10 is OH and R.sup.11 is not NH.sub.2;
[0356] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0357] (j) Z is N or CR.sup.12; and
[0358] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0359] A sixth aspect of the third embodiment is directed to a
compound represented by formula I-5
[0360] wherein
[0361] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0362] (b) R.sup.2 is hydrogen or CH.sub.3;
[0363] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl;
[0364] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0365] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, halogen, including F, Cl, Br, or I, with the provisos
that when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot
be H.
[0366] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0367] (g) X is H, OH, F, OCH.sub.3, Cl, Br, I, NH.sub.2, or
N.sub.3;
[0368] (h) Y is OH, H, CH.sub.3, vinyl, NH.sub.2, N.sub.3, CN, Cl,
Br, F, I, OC(O)CH.sub.3, OCH.sub.3;
[0369] (i) R.sup.10 is NH.sub.2 and R.sup.11 is H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R';
[0370] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0371] (j) Z is N or CR.sup.12; and
[0372] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0373] A seventh aspect of the third embodiment is directed to a
compound represented by formula I-5
[0374] wherein
[0375] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0376] (b) R.sup.2 is hydrogen or CH.sub.3; [0377] (c) R.sup.3a is
H and R.sup.3b is H, CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, or lower cycloalkyl;
[0378] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0379] (e) R.sup.5 is H, CN, CH.sub.2F, F, Cl, Br, or I; with the
proviso that X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5
cannot be H;
[0380] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0381] (g) X is H, OH, F, OCH.sub.3, F, Cl, Br, I, NH.sub.2 or
N.sub.3;
[0382] (h) Y is H, OH, CH.sub.3, F, Cl, Br, I, NH.sub.2 or N.sub.3,
OCH.sub.3, or OC(O)CH.sub.3;
[0383] (i) R.sup.10 is NH.sub.2 and R.sup.11 is H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R';
[0384] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0385] (j) Z is N or CR.sup.12; and
[0386] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0387] An eighth aspect of the third embodiment is directed to a
compound represented by formula I-5
[0388] wherein
[0389] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0390] (b) R.sup.2 is hydrogen;
[0391] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0392] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower
haloalkyl;
[0393] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0394] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0395] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0396] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0397] (i) R.sup.10 is NH.sub.2 and R.sup.11 is H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R';
[0398] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0399] (j) Z is N or CR.sup.12; and
[0400] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0401] A ninth aspect of the third embodiment is directed to a
compound represented by formula I-5
[0402] wherein
[0403] (a) R.sup.1 is hydrogen, methyl, phenyl, p-bromo-phenyl,
p-chloro-phenyl, p-fluorophenyl;
[0404] (b) R.sup.2 is hydrogen;
[0405] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0406] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, or
N-methyl-pyrrolidin-4-yl, lower haloalkyl, or di(lower
alkyl)amino-lower alkyl;
[0407] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0408] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0409] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0410] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0411] (i) R.sup.10 is NH.sub.2 and R.sup.11 is H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R',
[0412] CONH.sub.2, CONHR', CONR'.sub.2, CH.dbd.CHCO.sub.2H, or
CH.dbd.CHCO.sub.2R';
[0413] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0414] (j) Z is N or CR.sup.12; and
[0415] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0416] A tenth aspect of the third embodiment is directed to a
compound represented by formula I-6
##STR00012##
[0417] wherein
[0418] (a) R.sup.1 is hydrogen, n-alkyl; branched alkyl;
cycloalkyl; or aryl, which includes, but is not limited to, phenyl
or naphthyl, where phenyl or naphthyl are optionally substituted
with at least one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C.sub.1-6
haloalkyl, --N(R.sup.1').sub.2, C.sub.1-6 acylamino,
--NHSO.sub.2C.sub.1-6 alkyl, --SO.sub.2N(R.sup.1').sub.2,
COR.sup.1'', and --SO.sub.2C.sub.1-6 alkyl; (R.sup.1' is
independently hydrogen or alkyl, which includes, but is not limited
to, C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl,
R.sup.1'' is --OR' or --N(R.sup.1').sub.2);
[0419] (b) R.sup.2 is hydrogen or CH.sub.3;
[0420] (c) R.sup.3a and R.sup.3b are (i) independently selected
from hydrogen, C.sub.1-10 alkyl, cycloalkyl,
--(CH.sub.2).sub.c(NR.sup.3').sub.2, C.sub.1-6 hydroxyalkyl,
--CH.sub.2SH, --(CH.sub.2).sub.2S(O).sub.dMe,
--(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, (1H-indol-3-yl)methyl,
(1H-imidazol-4-yl)methyl, --(CH.sub.2).sub.eCOR.sup.3, aryl and
aryl C.sub.1-3 alkyl, said aryl groups optionally substituted with
a group selected from hydroxyl, C.sub.1-10 alkyl, C.sub.1-6 alkoxy,
halogen, nitro and cyano; (ii) R.sup.3a and R.sup.3b both are
C.sub.1-6 alkyl; (iii) R.sup.3a and R.sup.3b together are
(CH.sub.2).sub.f so as to form a spiro ring; (iv) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 2 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
--CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H, where R.sup.3' is independently
hydrogen or alkyl, which includes, but is not limited to,
C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl, R.sup.3''
is --OR' or --N(R.sup.3').sub.2);
[0421] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy or halogen,
C.sub.1-10 haloalkyl, C.sub.3-10 cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl,
aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted
aryl, or substituted heteroaryl;
[0422] (e) R.sup.5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl),
hydroxyl lower alkyl, i.e., --(CH.sub.2).sub.pOH, where p is 1-6,
including hydroxyl methyl (CH.sub.2OH), CH.sub.2F, N.sub.3,
CH.sub.2CN, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, alkyne (optionally substituted), or
halogen, including F, Cl, Br, or I, with the provisos that when X
is OH, base is cytosine and R.sup.6 is H, R.sup.5 cannot be N.sub.3
and when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F and B is a
purine base, R.sup.5 cannot be H;
[0423] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0424] (g) X is H, OH, F, OMe, Cl, Br, I, NH.sub.2, or N.sub.3;
[0425] (h) Y is OH, H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, vinyl, N.sub.3, CN, Cl, Br, F, I, NO.sub.2,
OC(O)O(C.sub.1-4alkyl), OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.2-4
alkynyl), OC(O)O(C.sub.2-4 alkenyl), OC.sub.1-10 haloalkyl,
O(aminoacyl), O(C.sub.1-10 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4
alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4
alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4
alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl), SO.sub.2
(C.sub.1-4 acyl), SO.sub.2 (C.sub.1-4 alkyl), SO.sub.2 (C.sub.2-4
alkynyl), SO.sub.2(C.sub.2-4 alkenyl), OS(O).sub.2(C.sub.1-4 acyl),
OS(O).sub.2(C.sub.1-4 alkyl), OS(O).sub.2(C.sub.2-4 alkenyl),
NH.sub.2, NH(C.sub.1-4 alkyl), NH(C.sub.2-4 alkenyl), NH(C.sub.2-4
alkynyl), NH(C.sub.1-4 acyl), N(C.sub.1-4 alkyl).sub.2,
N(C.sub.1-18 acyl).sub.2, wherein alkyl, alkynyl, alkenyl and vinyl
are optionally substituted by N.sub.3, CN, one to three halogen
(Cl, Br, F, I), NO.sub.2, C(O)O(C.sub.1-4 alkyl), C(O)O(C.sub.1-4
alkyl), C(O)O(C.sub.2-4 alkynyl), C(O)O(C.sub.2-4 alkenyl),
O(C.sub.1-4 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4 alkenyl),
S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4 alkynyl),
S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4 alkyl),
SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl), SO.sub.2(C.sub.1-4
acyl), SO.sub.2(C.sub.1-4 alkyl), SO.sub.2(C.sub.2-4 alkynyl),
SO.sub.2(C.sub.2-4 alkenyl), OS(O).sub.2(C.sub.1-4 acyl),
OS(O).sub.2(C.sub.1-4 alkyl), OS(O).sub.2(C.sub.2-4 alkenyl),
NH.sub.2, NH(C.sub.1-4 alkyl), NH(C.sub.2-4 alkenyl), NH(C.sub.2-4
alkynyl), NH(C.sub.1-4 acyl), N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-4
acyl).sub.2;
[0426] (i) R.sup.10 and R.sup.11 are independently H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R', with the
proviso that when R.sup.10 is OH and R.sup.11 is not NH.sub.2;
[0427] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0428] (j) Z is N or CR.sup.12; and
[0429] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0430] An eleventh aspect of the third embodiment is directed to a
compound represented by formula I-6
[0431] wherein
[0432] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0433] (b) R.sup.2 is hydrogen or CH.sub.3;
[0434] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl;
[0435] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0436] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, halogen, including F, Cl, Br, or I, with the provisos
that when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot
be H;
[0437] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0438] (g) X is H, OH, F, OCH.sub.3, Cl, Br, I, NH.sub.2, or
N.sub.3;
[0439] (h) Y is OH, H, CH.sub.3, vinyl, NH.sub.2, N.sub.3, CN, Cl,
Br, F, I, OC(O)CH.sub.3, OCH.sub.3;
[0440] (i) R.sup.10 and R.sup.11 are independently H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R', with the
proviso that when R.sup.10 is OH and R.sup.11 is not NH.sub.2;
[0441] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0442] (j) Z is N or CR.sup.12; and
[0443] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0444] A twelfth aspect of the third embodiment is directed to a
compound represented by formula I-6
[0445] wherein
[0446] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0447] (b) R.sup.2 is hydrogen or CH.sub.3;
[0448] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0449] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0450] (e) R.sup.5 is H, CN, CH.sub.2F, F, Cl, Br, or I, with the
provisos that when X is OH,
[0451] R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0452] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0453] (g) X is H, OH, F, OCH.sub.3, F, Cl, Br, I, NH.sub.2 or
N.sub.3;
[0454] (h) Y is H, OH, CH.sub.3, F, Cl, Br, I, NH.sub.2 or N.sub.3,
OCH.sub.3, or OC(O)CH.sub.3;
[0455] (i) R.sup.10 and R.sup.11 are independently H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R', with the
proviso that when R.sup.10 is OH and R.sup.11 is not NH.sub.2;
[0456] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0457] (j) Z is N or CR.sup.12; and
[0458] R.sup.12 is a H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0459] A thirteenth aspect of the third embodiment is directed to a
compound represented by formula I-6
[0460] wherein
[0461] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0462] (b) R.sup.2 is hydrogen;
[0463] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0464] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0465] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0466] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0467] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0468] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0469] (i) R.sup.10 and R.sup.11 are independently H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R', with the
proviso that when R.sup.10 is OH and R.sup.11 is not NH.sub.2;
[0470] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0471] (j) Z is N or CR.sup.12; and
[0472] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0473] A fourteenth aspect of the third embodiment is directed to a
compound represented by formula I-6
[0474] wherein
[0475] (a) R.sup.1 is hydrogen, methyl, phenyl, p-bromo-phenyl,
p-chloro-phenyl, p-fluorophenyl;
[0476] (b) R.sup.2 is hydrogen;
[0477] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0478] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0479] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0480] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0481] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0482] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0483] (i) R.sup.10 and R.sup.11 are independently H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R', with the
proviso that when R.sup.10 is OH and R.sup.11 is not NH.sub.2;
[0484] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0485] (j) Z is N or CR.sup.12; and
[0486] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0487] A fifteenth aspect of the third embodiment is directed to a
compound represented by formula I-6
[0488] wherein
[0489] (a) R.sup.1 is hydrogen, n-alkyl; branched alkyl;
cycloalkyl; or aryl, which includes, but is not limited to, phenyl
or naphthyl, where phenyl or naphthyl are optionally substituted
with at least one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C.sub.1-6
haloalkyl, --N(R.sup.1').sub.2, C.sub.1-6 acylamino,
--NHSO.sub.2C.sub.1-6 alkyl, --SO.sub.2N(R.sup.1').sub.2,
COR.sup.1'', and --SO.sub.2C.sub.1-6 alkyl; (R.sup.1' is
independently hydrogen or alkyl, which includes, but is not limited
to, C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl,
R.sup.1'' is OR' or --N(R.sup.1').sub.2);
[0490] (b) R.sup.2 is hydrogen or CH.sub.3;
[0491] (c) R.sup.3a and R.sup.3b are (i) independently selected
from hydrogen, C.sub.1-10 alkyl, cycloalkyl,
--(CH.sub.2).sub.c(NR.sup.3').sub.2, C.sub.1-6 hydroxyalkyl,
--CH.sub.2SH, --(CH.sub.2).sub.2S(O).sub.dMe,
--(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, (1H-indol-3-yl)methyl,
(1H-imidazol-4-yl)methyl, --(CH.sub.2).sub.eCOR.sup.3u, aryl and
aryl C.sub.1-3 alkyl, said aryl groups optionally substituted with
a group selected from hydroxyl, C.sub.1-10 alkyl, C.sub.1-6 alkoxy,
halogen, nitro and cyano; (ii) R.sup.3a and R.sup.3b both are
C.sub.1-6 alkyl; (iii) R.sup.3a and R.sup.3b together are
(CH.sub.2).sub.f so as to form a spiro ring; (iv) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 2 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
--CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H, where R.sup.3' is independently
hydrogen or alkyl, which includes, but is not limited to,
C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl, R.sup.3''
is --OR' or --N(R.sup.3').sub.2);
[0492] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy or halogen,
C.sub.1-10 haloalkyl, C.sub.3-10 cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl,
aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted
aryl, or substituted heteroaryl;
[0493] (e) R.sup.5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl),
hydroxyl lower alkyl, i.e., --(CH.sub.2).sub.pOH, where p is 1-6,
including hydroxyl methyl (CH.sub.2OH), CH.sub.2F, N.sub.3,
CH.sub.2CN, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, alkyne (optionally substituted), or
halogen, including F, Cl, Br, or I, with the provisos that when X
is OH, base is cytosine and R.sup.6 is H, R.sup.5 cannot be N.sub.3
and when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F and B is a
purine base, R.sup.5 cannot be H;
[0494] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0495] (g) X is H, OH, F, OMe, halogen, NH.sub.2, or N.sub.3;
[0496] (h) Y is OH, H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, vinyl, N.sub.3, CN, Cl, Br, F, I, NO.sub.2,
OC(O)O(C.sub.1-4alkyl), OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.2-4
alkynyl), OC(O)O(C.sub.2-4 alkenyl), OC.sub.1-10 haloalkyl,
O(aminoacyl), O(C.sub.1-10 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4
alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4
alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4
alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl), SO.sub.2
(C.sub.1-4 acyl), SO.sub.2 (C.sub.1-4 alkyl), SO.sub.2 (C.sub.2-4
alkynyl), SO.sub.2(C.sub.2-4 alkenyl), OS(O).sub.2(C.sub.1-4 acyl),
OS(O).sub.2(C.sub.1-4 alkyl), OS(O).sub.2(C.sub.2-4 alkenyl),
NH.sub.2, NH(C.sub.1-4 alkyl), NH(C.sub.2-4 alkenyl), NH(C.sub.2-4
alkynyl), NH(C.sub.1-4 acyl), N(C.sub.1-4 alkyl).sub.2,
N(C.sub.1-18 acyl).sub.2, wherein alkyl, alkynyl, alkenyl and vinyl
are optionally substituted by N.sub.3, CN, one to three halogen
(Cl, Br, F, I), NO.sub.2, C(O)O(C.sub.1-4 alkyl), C(O)O(C.sub.1-4
alkyl), C(O)O(C.sub.2-4 alkynyl), C(O)O(C.sub.2-4 alkenyl),
O(C.sub.1-4 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4 alkenyl),
S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4 alkynyl),
S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4 alkyl),
SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl), SO.sub.2(C.sub.1-4
acyl), SO.sub.2(C.sub.1-4 alkyl), SO.sub.2(C.sub.2-4 alkynyl),
SO.sub.2(C.sub.2-4 alkenyl), OS(O).sub.2(C.sub.1-4 acyl),
OS(O).sub.2(C.sub.1-4 alkyl), OS(O).sub.2(C.sub.2-4 alkenyl),
NH.sub.2, NH(C.sub.1-4 alkyl), NH(C.sub.2-4 alkenyl), NH(C.sub.2-4
alkynyl), NH(C.sub.1-4 acyl), N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-4
acyl).sub.2;
[0497] (i) R.sup.10 is NH.sub.2 and R.sup.11 is H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R';
[0498] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0499] (j) Z is N or CR.sup.12; and
[0500] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0501] An sixteenth aspect of the third embodiment is directed to a
compound represented by formula I-6
[0502] wherein
[0503] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0504] (b) R.sup.2 is hydrogen or CH.sub.3;
[0505] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl;
[0506] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0507] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, halogen, including F, Cl, Br, or I, with the provisos
that when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot
be H;
[0508] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0509] (g) X is H, OH, F, OCH.sub.3, Cl, Br, I, NH.sub.2, or
N.sub.3;
[0510] (h) Y is OH, H, CH.sub.3, vinyl, NH.sub.2, N.sub.3, CN, Cl,
Br, F, I, OC(O)CH.sub.3, OCH.sub.3;
[0511] (i) R.sup.10 is NH.sub.2 and R.sup.11 is H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R';
[0512] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0513] (j) Z is N or CR.sup.12; and
[0514] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0515] A seventeenth aspect of the third embodiment is directed to
a compound represented by formula I-6
[0516] wherein
[0517] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0518] (b) R.sup.2 is hydrogen or CH.sub.3;
[0519] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0520] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0521] (e) R.sup.5 is H, CN, CH.sub.2F, F, Cl, Br, or I, with the
provisos that when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F,
R.sup.5 cannot be H;
[0522] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0523] (g) X is H, OH, F, OCH.sub.3, F, Cl, Br, I, NH.sub.2 or
N.sub.3;
[0524] (h) Y is H, OH, CH.sub.3, F, Cl, Br, I, NH.sub.2 or N.sub.3,
OCH.sub.3, or OC(O)CH.sub.3;
[0525] (i) R.sup.10 is NH.sub.2 and R.sup.11 is H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R';
[0526] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0527] (j) Z is N or CR.sup.12; and
[0528] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0529] An eighteenth aspect of the third embodiment is directed to
a compound represented by formula I-6
[0530] wherein
[0531] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0532] (b) R.sup.2 is hydrogen;
[0533] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0534] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0535] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0536] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0537] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0538] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0539] (i) R.sup.10 is NH.sub.2 and R.sup.11 is H, F, Br, I, OH,
OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR',
CONR'.sub.2, CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R';
[0540] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0541] (j) Z is N or CR.sup.12; and
[0542] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0543] A nineteenth aspect of the third embodiment is directed to a
compound represented by formula I-6
[0544] wherein
[0545] (a) R.sup.1 is hydrogen, methyl, phenyl, p-bromo-phenyl,
p-chloro-phenyl, p-fluorophenyl;
[0546] (b) R.sup.2 is hydrogen;
[0547] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0548] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0549] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0550] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0551] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0552] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0553] (i) R.sup.10 is NH.sub.2 and R.sup.11 are independently H,
F, Br, I, OH, OR', NH.sub.2, NHR', NR'.sub.2, CO.sub.2R',
CONH.sub.2, CONHR', CONR'.sub.2, CH.dbd.CHCO.sub.2H, or
CH.dbd.CHCO.sub.2R';
[0554] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0555] (j) Z is N or CR.sup.12; and
[0556] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0557] A fourth embodiment of the invention is directed to a
compound represented by formula I in which the base is a structure
represented by formula c above, where R.sup.11 is H and R.sup.2,
R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, X, and Y are defined
in the Summary of the Invention section above.
[0558] A first aspect of the fourth embodiment is directed to a
compound represented by formula I-7
##STR00013##
[0559] wherein
[0560] (a) R.sup.1 is hydrogen, n-alkyl; branched alkyl;
cycloalkyl; or aryl, which includes, but is not limited to, phenyl
or naphthyl, where phenyl or naphthyl are optionally substituted
with at least one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C.sub.1-6
haloalkyl, --N(R.sup.1').sub.2, C.sub.1-6 acylamino,
--NHSO.sub.2C.sub.1-6 alkyl, --SO.sub.2N(R.sup.1').sub.2,
COR.sup.1'', and --SO.sub.2C.sub.1-6 alkyl; (R.sup.1' is
independently hydrogen or alkyl, which includes, but is not limited
to, C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl,
R.sup.1'' is --OR' or --N(R.sup.1').sub.2);
[0561] (b) R.sup.2 is hydrogen or CH.sub.3;
[0562] (c) R.sup.3a and R.sup.3b are (i) independently selected
from hydrogen, C.sub.1-10 alkyl, cycloalkyl,
--(CH.sub.2).sub.c(NR.sup.3').sub.2, C.sub.1-6 hydroxyalkyl,
--CH.sub.2SH, --(CH.sub.2).sub.2S(O).sub.dMe,
--(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, (1H-indol-3-yl)methyl,
(1H-imidazol-4-yl)methyl, --(CH.sub.2).sub.eCOR.sup.3'', aryl and
aryl C.sub.1-3 alkyl, said aryl groups optionally substituted with
a group selected from hydroxyl, C.sub.1-10 alkyl, C.sub.1-6 alkoxy,
halogen, nitro and cyano; (ii) R.sup.3a and R.sup.3b both are
C.sub.1-6 alkyl; (iii) R.sup.3a and R.sup.3b together are
(CH.sub.2).sub.f so as to form a spiro ring; (iv) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 2 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
--CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H, where R.sup.3' is independently
hydrogen or alkyl, which includes, but is not limited to,
C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl, R.sup.3''
is --OR' or --N(R.sup.3').sub.2);
[0563] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy or halogen,
C.sub.1-10 haloalkyl, C.sub.3-10 cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl,
aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted
aryl, or substituted heteroaryl;
[0564] (e) R.sup.5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl),
hydroxyl lower alkyl, i.e., --(CH.sub.2).sub.pOH, where p is 1-6,
including hydroxyl methyl (CH.sub.2OH), CH.sub.2F, N.sub.3,
CH.sub.2CN, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, alkyne (optionally substituted), or
halogen, including F, Cl, Br, or I, with the provisos that when X
is OH, base is cytosine and R.sup.6 is H, R.sup.5 cannot be N.sub.3
and when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F and B is a
purine base, R.sup.5 cannot be H;
[0565] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0566] (g) X is H, OH, F, OMe, halogen, NH.sub.2, or N.sub.3;
[0567] (h) Y is OH, H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, vinyl, N.sub.3, CN, Cl, Br, F, I, NO.sub.2,
OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.2-4
alkynyl), OC(O)O(C.sub.2-4 alkenyl), OC.sub.1-10 haloalkyl,
O(aminoacyl), O(C.sub.1-10 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4
alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4
alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4
alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-18 acyl).sub.2, wherein alkyl,
alkynyl, alkenyl and vinyl are optionally substituted by N.sub.3,
CN, one to three halogen (Cl, Br, F, I), NO.sub.2, C(O)O(C.sub.1-4
alkyl), C(O)O(C.sub.1-4 alkyl), C(O)O(C.sub.2-4 alkynyl),
C(O)O(C.sub.2-4 alkenyl), O(C.sub.1-4 acyl), O(C.sub.1-4 alkyl),
O(C.sub.2-4 alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl),
S(C.sub.2-4 alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl),
SO(C.sub.1-4 alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-4 acyl).sub.2;
[0568] (i) R.sup.10 is H, F, Cl, Br, I, OH, OR', SH, SR', NH.sub.2,
NHR', NR'.sub.2, lower alkyl of C.sub.1-C.sub.6, halogenated (F,
Cl, Br, I) lower alkyl of C.sub.1-C.sub.6, lower alkenyl of
C.sub.2-C.sub.6, halogenated (F, Cl, Br, I) lower alkenyl of
C.sub.2-C.sub.6, lower alkynyl of C.sub.2-C.sub.6 such as
C.ident.CH, halogenated (F, Cl, Br, I) lower alkynyl of
C.sub.2-C.sub.6, lower alkoxy of C.sub.1-C.sub.6, halogenated (F,
Cl, Br, I) lower alkoxy of C.sub.1-C.sub.6, CO.sub.2H, CO.sub.2R',
CONH.sub.2, CONHR', CONR'.sub.2, CH.dbd.CHCO.sub.2H, or
CH.dbd.CHCO.sub.2R',
[0569] wherein R' is an optionally substituted alkyl, which
includes, but is not limited to, an optionally substituted
C.sub.1-20 alkyl, an optionally substituted C.sub.1-10 alkyl, an
optionally substituted lower alkyl; an optionally substituted
cycloalkyl; an optionally substituted alkynyl of C.sub.2-C.sub.6,
an optionally substituted lower alkenyl of C.sub.2-C.sub.6, or
optionally substituted acyl, which includes but is not limited to
C(O) alkyl, C(O)(C.sub.1-20 alkyl), C(O)(C.sub.1-10 alkyl), or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0570] (j) Z is N or CR.sup.12; and
[0571] R.sup.12 is H, halogen (including F, Cl, Br, I), OH, OR',
SH, SR', NH.sub.2, NHR', NR'.sub.2, NO.sub.2 lower alkyl of
C.sub.1-C.sub.6, halogenated (F, Cl, Br, I) lower alkyl of
C.sub.1-C.sub.6, lower alkenyl of C.sub.2-C.sub.6, halogenated (F,
Cl, Br, I) lower alkenyl of C.sub.2-C.sub.6, lower alkynyl of
C.sub.2-C.sub.6, halogenated (F, Cl, Br, I) lower alkynyl of
C.sub.2-C.sub.6, lower alkoxy of C.sub.1-C.sub.6, halogenated (F,
Cl, Br, I) lower alkoxy of C.sub.1-C.sub.6, CO.sub.2H, CO.sub.2R',
CONH.sub.2, CONHR', CONR'.sub.2, CH.dbd.CHCO.sub.2H, or
CH.dbd.CHCO.sub.2R; with the proviso that R.sup.12 is not a: (i)
--C.ident.C--H, (ii) --C.dbd.CH.sub.2, or (iii) --NO.sub.2.
[0572] A second aspect of the fourth embodiment is directed to a
compound represented by formula I-7
[0573] wherein
[0574] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0575] (b) R.sup.2 is hydrogen or CH.sub.3;
[0576] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl;
[0577] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0578] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, halogen, including F, Cl, Br, or I, with the provisos
that when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot
be H.
[0579] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0580] (g) X is H, OH, F, OCH.sub.3, halogen, NH.sub.2, or
N.sub.3;
[0581] (h) Y is OH, H, CH.sub.3, vinyl, NH.sub.2, N.sub.3, CN, Cl,
Br, F, I, OC(O)CH.sub.3, OCH.sub.3;
[0582] (i) R.sup.10 is H, F, Br, I, OH, OR', NH.sub.2, NHR',
NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R',
[0583] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0584] (j) Z is N or CR.sup.12; and
[0585] R.sup.12 is H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'; with the proviso that
R.sup.12 is not a: (i) --C.ident.C--H, (ii) --C.dbd.CH.sub.2, or
(iii) --NO.sub.2.
[0586] A third aspect of the third embodiment is directed to a
compound represented by formula I-7
[0587] wherein
[0588] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0589] (b) R.sup.2 is hydrogen or CH.sub.3;
[0590] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0591] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0592] (e) R.sup.5 is H, CN, CH.sub.2F, F, Cl, Br, or I; with the
proviso that X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5
cannot be H;
[0593] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0594] (g) X is H, OH, F, OCH.sub.3, F, Cl, Br, I, NH.sub.2 or
N.sub.3;
[0595] (h) Y is H, OH, CH.sub.3, F, Cl, Br, I, NH.sub.2 or N.sub.3,
OCH.sub.3, or OC(O)CH.sub.3;
[0596] (i) R.sup.10 is H, F, Br, I, OH, OR', NH.sub.2, NHR',
NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R',
[0597] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0598] (j) Z is N or CR.sup.12; and
[0599] R.sup.12 is H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'; with the proviso that
R.sup.12 is not a: (i) --C.ident.C--H, (ii) --C.dbd.CH.sub.2, or
(iii) --NO.sub.2.
[0600] A fourth aspect of the fourth embodiment is directed to a
compound represented by formula I-7
[0601] wherein
[0602] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0603] (b) R.sup.2 is hydrogen;
[0604] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0605] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0606] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0607] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0608] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0609] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0610] (i) R.sup.10 and R.sup.11 H, F, Br, I, OH, OR', NH.sub.2,
NHR', NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R',
[0611] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0612] (j) Z is N or CR.sup.12; and
[0613] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'; with the proviso that
R.sup.12 is not a: (i) --C.ident.C--H, (ii) --C.dbd.CH.sub.2, or
(iii) --NO.sub.2.
[0614] A fifth aspect of the fourth embodiment is directed to a
compound represented by formula I-7
[0615] wherein
[0616] (a) R.sup.1 is hydrogen, methyl, phenyl, p-bromo-phenyl,
p-chloro-phenyl, p-fluorophenyl;
[0617] (b) R.sup.2 is hydrogen;
[0618] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0619] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0620] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0621] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0622] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0623] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0624] (i) R.sup.10 is H, F, Br, I, OH, OR', NH.sub.2, NHR',
NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R',
[0625] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0626] (j) Z is N or CR.sup.12; and
[0627] R.sup.12 is H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'.
[0628] A sixth aspect of the fourth embodiment is directed to a
compound represented by formula I-8
##STR00014##
[0629] wherein
[0630] (a) R.sup.1 is hydrogen, n-alkyl; branched alkyl;
cycloalkyl; or aryl, which includes, but is not limited to, phenyl
or naphthyl, where phenyl or naphthyl are optionally substituted
with at least one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C.sub.1-6
haloalkyl, --N(R.sup.1').sub.2, C.sub.1-6 acylamino,
--NHSO.sub.2C.sub.1-6 alkyl, --SO.sub.2N(R.sup.1').sub.2,
COR.sup.1'', and --SO.sub.2C.sub.1-6 alkyl; (R.sup.1' is
independently hydrogen or alkyl, which includes, but is not limited
to, C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl,
R.sup.1'' is --OR' or --N(R.sup.1').sub.2);
[0631] (b) R.sup.2 is hydrogen or CH.sub.3;
[0632] (c) R.sup.3a and R.sup.3b are (i) independently selected
from hydrogen, C.sub.1-10 alkyl, cycloalkyl,
--(CH.sub.2).sub.c(NR.sup.3').sub.2, C.sub.1-6 hydroxyalkyl,
--CH.sub.2SH, --(CH.sub.2).sub.2S(O).sub.dMe,
--(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, (1H-indol-3-yl)methyl,
(1H-imidazol-4-yl)methyl, --(CH.sub.2).sub.eCOR.sup.3'', aryl and
aryl C.sub.1-3 alkyl, said aryl groups optionally substituted with
a group selected from hydroxyl, C.sub.1-10 alkyl, C.sub.1-6 alkoxy,
halogen, nitro and cyano; (ii) R.sup.3a and R.sup.3b both are
C.sub.1-6 alkyl; (iii) R.sup.3a and R.sup.3b together are
(CH.sub.2).sub.f so as to form a spiro ring; (iv) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 2 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
--CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H, where R.sup.3' is independently
hydrogen or alkyl, which includes, but is not limited to,
C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl, R.sup.3''
is --OR' or --N(R.sup.3').sub.2);
[0633] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy or halogen,
C.sub.1-10 haloalkyl, C.sub.3-10 cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl,
aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted
aryl, or substituted heteroaryl;
[0634] (e) R.sup.5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl),
hydroxyl lower alkyl, i.e., --(CH.sub.2).sub.pOH, where p is 1-6,
including hydroxyl methyl (CH.sub.2OH), CH.sub.2F, N.sub.3,
CH.sub.2CN, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, alkyne (optionally substituted), or
halogen, including F, Cl, Br, or I, with the provisos that when X
is OH, base is cytosine and R.sup.6 is H, R.sup.5 cannot be N.sub.3
and when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F and B is a
purine base, R.sup.5 cannot be H;
[0635] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0636] (g) X is H, OH, F, OMe, halogen, NH.sub.2, or N.sub.3;
[0637] (h) Y is OH, H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, vinyl, N.sub.3, CN, Cl, Br, F, I, NO.sub.2,
OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.2-4 alkynyl),
OC(O)O(C.sub.2-4 alkenyl), OC.sub.1-10 haloalkyl, O(aminoacyl),
O(C.sub.1-10 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4 alkenyl),
S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4 alkynyl),
S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4 alkyl),
SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl), SO.sub.2(C.sub.1-4
acyl), SO.sub.2(C.sub.1-4 alkyl), SO.sub.2(C.sub.2-4 alkynyl),
SO.sub.2(C.sub.2-4 alkenyl), OS(O).sub.2(C.sub.1-4 acyl),
OS(O).sub.2(C.sub.1-4 alkyl), OS(O).sub.2(C.sub.2-4 alkenyl),
NH.sub.2, NH(C.sub.1-4 alkyl), NH(C.sub.2-4 alkenyl), NH(C.sub.2-4
alkynyl), NH(C.sub.1-4 acyl), N(C.sub.1-4 alkyl).sub.2,
N(C.sub.1-18 acyl).sub.2, wherein alkyl, alkynyl, alkenyl and vinyl
are optionally substituted by N.sub.3, CN, one to three halogen
(Cl, Br, F, I), NO.sub.2, C(O)O(C.sub.1-4 alkyl), C(O)O(C.sub.1-4
alkyl), C(O)O(C.sub.2-4 alkynyl), C(O)O(C.sub.2-4 alkenyl),
O(C.sub.1-4 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4 alkenyl),
S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4 alkynyl),
S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4 alkyl),
SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl), SO.sub.2(C.sub.1-4
acyl), SO.sub.2(C.sub.1-4 alkyl), SO.sub.2(C.sub.2-4 alkynyl),
SO.sub.2(C.sub.2-4 alkenyl), OS(O).sub.2(C.sub.1-4 acyl),
OS(O).sub.2(C.sub.1-4 alkyl), OS(O).sub.2(C.sub.2-4 alkenyl),
NH.sub.2, NH(C.sub.1-4 alkyl), NH(C.sub.2-4 alkenyl), NH(C.sub.2-4
alkynyl), NH(C.sub.1-4 acyl), N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-4
acyl).sub.2;
[0638] (i) R.sup.10 is H, F, Br, I, OH, OR', NH.sub.2, NHR',
NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R',
[0639] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0640] (j) Z is N or CR.sup.12; and
[0641] R.sup.12 is H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'; with the proviso that
when base is represented by the structure c with R.sup.11 being
hydrogen, R.sup.12 is not a: (i) --C.ident.C--H, (ii)
--C.dbd.CH.sub.2, or (iii) --NO.sub.2.
[0642] A seventh aspect of the fourth embodiment is directed to a
compound represented by formula I-8
[0643] wherein
[0644] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0645] (b) R.sup.2 is hydrogen or CH.sub.3;
[0646] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl;
[0647] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0648] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, halogen, including F, Cl, Br, or I, with the provisos
that when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot
be H;
[0649] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0650] (g) X is H, OH, F, OCH.sub.3, halogen, NH.sub.2, or
N.sub.3;
[0651] (h) Y is OH, H, CH.sub.3, vinyl, NH.sub.2, N.sub.3, CN, Cl,
Br, F, I, OC(O)CH.sub.3, OCH.sub.3;
[0652] (i) R.sup.10 is H, F, Br, I, OH, OR', NH.sub.2, NHR',
NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R',
[0653] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0654] (j) Z is N or CR.sup.12; and
[0655] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'; with the proviso that
R.sup.12 is not a: (i) --C.ident.C--H, (ii) --C.dbd.CH.sub.2, or
(iii) --NO.sub.2.
[0656] An eighth aspect of the fourth embodiment is directed to a
compound represented by formula I-8
[0657] wherein
[0658] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0659] (b) R.sup.2 is hydrogen or CH.sub.3;
[0660] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0661] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0662] (e) R.sup.5 is H, CN, CH.sub.2F, F, Cl, Br, or I, with the
provisos that when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F,
R.sup.5 cannot be H;
[0663] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0664] (g) X is H, OH, F, OCH.sub.3, F, Cl, Br, I, NH.sub.2 or
N.sub.3;
[0665] (h) Y is H, OH, CH.sub.3, F, Cl, Br, I, NH.sub.2 or N.sub.3,
OCH.sub.3, or OC(O)CH.sub.3;
[0666] (i) R.sup.10 is H, F, Br, I, OH, OR', NH.sub.2, NHR',
NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R',
[0667] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0668] (j) Z is N or CR.sup.12; and
[0669] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'; with the proviso that
R.sup.12 is not a: (i) --C.ident.C--H, (ii) --C.dbd.CH.sub.2, or
(iii) --NO.sub.2.
[0670] A ninth aspect of the fourth embodiment is directed to a
compound represented by formula I-8
[0671] wherein
[0672] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0673] (b) R.sup.2 is hydrogen;
[0674] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0675] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0676] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0677] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0678] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0679] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0680] (i) R.sup.10 is H, F, Br, I, OH, OR', NH.sub.2, NHR',
NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R',
[0681] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0682] (j) Z is N or CR.sup.12; and
[0683] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'; with the proviso that
R.sup.12 is not a: (i) --C.ident.C--H, (ii) --C.dbd.CH.sub.2, or
(iii) --NO.sub.2.
[0684] A tenth aspect of the fourth embodiment is directed to a
compound represented by formula I-8
[0685] wherein
[0686] (a) R.sup.1 is hydrogen, methyl, phenyl, p-bromo-phenyl,
p-chloro-phenyl, p-fluorophenyl;
[0687] (b) R.sup.2 is hydrogen;
[0688] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0689] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0690] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0691] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0692] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0693] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0694] (i) R.sup.10 is H, F, Br, I, OH, OR', NH.sub.2, NHR',
NR'.sub.2, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R',
[0695] wherein R' is a lower alkyl, a lower cycloalkyl, or
C(O)(lower alkyl) or alternatively, in the instance of NR'.sub.2,
each R' comprise at least one C atom that are joined to form a
heterocycle comprising at least two carbon atoms; and
[0696] (j) Z is N or CR.sup.12; and
[0697] R.sup.12 is an H, halogen (including F, Cl, Br, I), OR',
NH.sub.2, NHR', NR'.sub.2, NO.sub.2, lower alkyl of
C.sub.1-C.sub.6, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, or CH.dbd.CHCO.sub.2R'; with the proviso that
R.sup.12 is not a: (i) --C.ident.C--H, (ii) --C.dbd.CH.sub.2, or
(iii) --NO.sub.2.
[0698] A fifth embodiment of the invention is directed to a
compound represented by formula I in which the base is a structure
represented by formula d above, wherein R.sup.1, R.sup.2, R.sup.3a,
R.sup.3b, R.sup.4, R.sup.5, R.sup.6, X, and Y are defined in the
Summary of the Invention section above.
[0699] The first aspect of the fifth embodiment is directed to a
compound represented by formula I-9
##STR00015##
[0700] wherein
[0701] (a) R.sup.1 is hydrogen, n-alkyl; branched alkyl;
cycloalkyl; or aryl, which includes, but is not limited to, phenyl
or naphthyl, where phenyl or naphthyl are optionally substituted
with at least one of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C.sub.1-6
haloalkyl, --N(R.sup.1').sub.2, C.sub.1-6 acylamino,
--NHSO.sub.2C.sub.1-6 alkyl, --SO.sub.2N(R.sup.1').sub.2,
COR.sup.1'', and --SO.sub.2C.sub.1-6 alkyl; (R.sup.1' is
independently hydrogen or alkyl, which includes, but is not limited
to, C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl,
R.sup.1'' is --OR' or --N(R.sup.1').sub.2);
[0702] (b) R.sup.2 is hydrogen or CH.sub.3;
[0703] (c) R.sup.3a and R.sup.3b are (i) independently selected
from hydrogen, C.sub.1-10 alkyl, cycloalkyl,
--(CH.sub.2).sub.c(NR.sup.3').sub.2, C.sub.1-6 hydroxyalkyl,
--CH.sub.2SH, --(CH.sub.2).sub.2S(O).sub.dMe,
--(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, (1H-indol-3-yl)methyl,
(1H-imidazol-4-yl)methyl, --(CH.sub.2).sub.eCOR.sup.3'', aryl and
aryl C.sub.1-3 alkyl, said aryl groups optionally substituted with
a group selected from hydroxyl, C.sub.1-10 alkyl, C.sub.1-6 alkoxy,
halogen, nitro and cyano; (ii) R.sup.3a and R.sup.3b both are
C.sub.1-6 alkyl; (iii) R.sup.3a and R.sup.3b together are
(CH.sub.2).sub.f so as to form a spiro ring; (iv) R.sup.3a is
hydrogen and R.sup.3b and R.sup.2 together are (CH.sub.2).sub.n so
as to form a cyclic ring that includes the adjoining N and C atoms
(v) R.sup.3b is hydrogen and R.sup.3a and R.sup.2 together are
(CH.sub.2).sub.n so as to form a cyclic ring that includes the
adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to
3, f is 2 to 5, n is 2 to 4, and where R.sup.3' is independently
hydrogen or C.sub.1-6 alkyl and R.sup.3'' is --OR' or
--N(R.sup.3').sub.2); (vi) R.sup.3a is H and R.sup.3b is H,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl; or (viii) R.sup.3a is CH.sub.3,
--CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H, where R.sup.3' is independently
hydrogen or alkyl, which includes, but is not limited to,
C.sub.1-20 alkyl, C.sub.1-10 alkyl, or C.sub.1-6 alkyl, R.sup.3''
is --OR' or --N(R.sup.3').sub.2);
[0704] (d) R.sup.4 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkyl
optionally substituted with a lower alkyl, alkoxy or halogen,
C.sub.1-10 haloalkyl, C.sub.3-10 cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl,
aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted
aryl, or substituted heteroaryl;
[0705] (e) R.sup.5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl),
hydroxyl lower alkyl, i.e., --(CH.sub.2).sub.pOH, where p is 1-6,
including hydroxyl methyl (CH.sub.2OH), CH.sub.2F, N.sub.3,
CH.sub.2CN, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, alkyne (optionally substituted), or
halogen, including F, Cl, Br, or I, with the provisos that when X
is OH, base is cytosine and R.sup.6 is H, R.sup.5 cannot be N.sub.3
and when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F and B is a
purine base, R.sup.5 cannot be H;
[0706] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0707] (g) X is H, OH, F, OMe, halogen, NH.sub.2, or N.sub.3;
[0708] (h) Y is OH, H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, vinyl, N.sub.3, CN, Cl, Br, F, I, NO.sub.2,
OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.1-4 alkyl), OC(O)O(C.sub.2-4
alkynyl), OC(O)O(C.sub.2-4 alkenyl), OC.sub.1-10 haloalkyl,
O(aminoacyl), O(C.sub.1-10 acyl), O(C.sub.1-4 alkyl), O(C.sub.2-4
alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl), S(C.sub.2-4
alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl), SO(C.sub.1-4
alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-18 acyl).sub.2, wherein alkyl,
alkynyl, alkenyl and vinyl are optionally substituted by N.sub.3,
CN, one to three halogen (Cl, Br, F, I), NO.sub.2, C(O)O(C.sub.1-4
alkyl), C(O)O(C.sub.1-4 alkyl), C(O)O(C.sub.2-4 alkynyl),
C(O)O(C.sub.2-4 alkenyl), O(C.sub.1-4 acyl), O(C.sub.1-4 alkyl),
O(C.sub.2-4 alkenyl), S(C.sub.1-4 acyl), S(C.sub.1-4 alkyl),
S(C.sub.2-4 alkynyl), S(C.sub.2-4 alkenyl), SO(C.sub.1-4 acyl),
SO(C.sub.1-4 alkyl), SO(C.sub.2-4 alkynyl), SO(C.sub.2-4 alkenyl),
SO.sub.2(C.sub.1-4 acyl), SO.sub.2(C.sub.1-4 alkyl),
SO.sub.2(C.sub.2-4 alkynyl), SO.sub.2(C.sub.2-4 alkenyl),
OS(O).sub.2(C.sub.1-4 acyl), OS(O).sub.2(C.sub.1-4 alkyl),
OS(O).sub.2(C.sub.2-4 alkenyl), NH.sub.2, NH(C.sub.1-4 alkyl),
NH(C.sub.2-4 alkenyl), NH(C.sub.2-4 alkynyl), NH(C.sub.1-4 acyl),
N(C.sub.1-4 alkyl).sub.2, N(C.sub.1-4 acyl).sub.2.
[0709] A second aspect of the fifth embodiment is directed to a
compound represented by formula I-9
[0710] wherein
[0711] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0712] (b) R.sup.2 is hydrogen or CH.sub.3;
[0713] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl;
[0714] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0715] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, halogen, including F, Cl, Br, or I, with the provisos
that when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot
be H.
[0716] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0717] (g) X is H, OH, F, OCH.sub.3, halogen, NH.sub.2, or
N.sub.3;
[0718] (h) Y is OH, H, CH.sub.3, vinyl, NH.sub.2, N.sub.3, CN, Cl,
Br, F, I, OC(O)CH.sub.3, OCH.sub.3;
[0719] A third aspect of the fifth embodiment is directed to a
compound represented by formula I-9
[0720] wherein
[0721] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0722] (b) R.sup.2 is hydrogen or CH.sub.3;
[0723] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0724] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0725] (e) R.sup.5 is H, CN, CH.sub.2F, F, Cl, Br, or I; with the
proviso that X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5
cannot be H;
[0726] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0727] (g) X is H, OH, F, OCH.sub.3, F, Cl, Br, I, NH.sub.2 or
N.sub.3;
[0728] (h) Y is H, OH, CH.sub.3, F, Cl, Br, I, NH.sub.2 N.sub.3,
OCH.sub.3, or OC(O)CH.sub.3;
[0729] A fourth aspect of the fifth embodiment is directed to a
compound represented by formula I-9
[0730] wherein
[0731] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0732] (b) R.sup.2 is hydrogen;
[0733] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0734] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0735] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0736] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0737] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0738] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0739] A fifth aspect of the fifth embodiment is directed to a
compound represented by formula I-9
[0740] wherein
[0741] (a) R.sup.1 is hydrogen, methyl, phenyl, p-bromo-phenyl,
p-chloro-phenyl, p-fluorophenyl;
[0742] (b) R.sup.2 is hydrogen;
[0743] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0744] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0745] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0746] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0747] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0748] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0749] A sixth aspect of the fifth embodiment is directed to a
compound represented by formula I-10
##STR00016##
[0750] wherein
[0751] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
or a substituted or unsubstituted phenyl, where the substitutent of
the substituted phenyl is at least one of a CH.sub.3, OCH.sub.3, F,
Cl, Br, I, nitro, cyano, and a CH.sub.3-qX.sub.q, where X is F, Cl,
Br, or I, and q is 1-3;
[0752] (b) R.sup.2 is hydrogen or CH.sub.3;
[0753] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl or R.sup.3a is CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3,
CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl and R.sup.3b is H;
[0754] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0755] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, N.sub.3, CH.sub.2CN, CH.sub.2N.sub.3, CH.sub.2NH.sub.2,
CH.sub.2NHCH.sub.3, CH.sub.2N(CH.sub.3).sub.2, halogen, including
F, Cl, Br, or I, with the provisos that when X is OH, R.sup.6 is
CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0756] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0757] (g) X is H, OH, F, OCH.sub.3, Cl, Br, I, NH.sub.2, or
N.sub.3;
[0758] (h) Y is OH, H, CH.sub.3, vinyl, N.sub.3, CN, Cl, Br, F, I,
OC(O)CH.sub.3, OCH.sub.3, NH.sub.2, NHCH.sub.3, NH(vinyl),
NH(acetyl), NH(C(O)CH.sub.3), N(CH.sub.3).sub.2,
N(C(O)CH.sub.3).sub.2;
[0759] A seventh aspect of the fifth embodiment is directed to a
compound represented by formula I-10
[0760] wherein
[0761] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0762] (b) R.sup.2 is hydrogen or CH.sub.3;
[0763] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2C(O)NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl,
CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or
lower cycloalkyl;
[0764] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0765] (e) R.sup.5 is H, CN, CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2F, halogen, including F, Cl, Br, or I, with the provisos
that when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot
be H;
[0766] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
F, or CN;
[0767] (g) X is H, OH, F, OCH.sub.3, Cl, Br, I, NH.sub.2, or
N.sub.3; and
[0768] (h) Y is OH, H, CH.sub.3, vinyl, NH.sub.2, N.sub.3, CN, Cl,
Br, F, I, OC(O)CH.sub.3, OCH.sub.3.
[0769] An eighth aspect of the fifth embodiment is directed to a
compound represented by formula I-10
[0770] wherein
[0771] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0772] (b) R.sup.2 is hydrogen or CH.sub.3;
[0773] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0774] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0775] (e) R.sup.5 is H, CN, CH.sub.2F, F, Cl, Br, or I, with the
provisos that when X is OH, R.sup.6 is CH.sub.3 or CH.sub.2F,
R.sup.5 cannot be H;
[0776] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0777] (g) X is H, OH, F, OCH.sub.3, F, Cl, Br, I, NH.sub.2 or
N.sub.3;
[0778] (h) Y is H, OH, CH.sub.3, F, Cl, Br, I, NH.sub.2 or N.sub.3,
OCH.sub.3, or OC(O)CH.sub.3;
[0779] A ninth aspect of the fifth embodiment is directed to a
compound represented by formula I-10
[0780] wherein
[0781] (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl,
phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl,
p-fluorophenyl;
[0782] (b) R.sup.2 is hydrogen;
[0783] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0784] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0785] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0786] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0787] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0788] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3;
[0789] A tenth aspect of the fifth embodiment is directed to a
compound represented by formula I-10
[0790] wherein
[0791] (a) R.sup.1 is hydrogen, methyl, phenyl, p-bromo-phenyl,
p-chloro-phenyl, p-fluorophenyl;
[0792] (b) R.sup.2 is hydrogen;
[0793] (c) R.sup.3a is H and R.sup.3b is H, CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl;
[0794] (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr,
.sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl,
N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,
N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl,
or di(lower alkyl)amino-lower alkyl;
[0795] (e) R.sup.5 is H, with the provisos that when X is OH,
R.sup.6 is CH.sub.3 or CH.sub.2F, R.sup.5 cannot be H;
[0796] (f) R.sup.6 is H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3,
or F;
[0797] (g) X is H, OH, OCH.sub.3, F, NH.sub.2 or N.sub.3;
[0798] (h) Y is OH, NH.sub.2, OCH.sub.3, or OC(O)CH.sub.3.
[0799] The following tables contain numeric identifiers associated
with various substituent designators that should be viewed in light
of the accompanying structure. These structures are contemplated
species of the various aspects of the disclosed embodiments and are
not intended to be limiting on full breadth of the contemplated
compound represented by the structure of formula I. However, it is
contemplated that any one of the exemplified nucleoside bases can
be used in combination with any one of contemplated species that
specify a particular combination of R.sup.1, R.sup.2, R.sup.3a,
R.sup.3b, R.sup.4, R.sup.5, R.sup.6, X, and Y. In each of the
presented tables, the phosphoramidate substituent containing the
substituents R.sup.3a and R.sup.3b are depicted without reference
to stereochemical structure (cf. structures I-1, I-3, I-5, I-7, and
I-9 above). It is contemplated that the compounds recited below
embody compounds in which R.sup.3a projects toward the viewer while
R.sup.3b projects away from the viewer (cf. structures I-2, I-4,
I-6, I-8, and I-10). Moreover, it is contemplated that the
compounds recited below also embody compounds in which R.sup.3a
projects away from the viewer while R.sup.3b projects towards the
viewer. Not meant to be limiting, however, it is contemplated that
preferred compounds are those in which R.sup.3a projects towards
the viewer and R.sup.3b projects away from the viewer such that the
natural L-amino acid (S)-configuration is presented. Additionally,
the inventors recognize that the phosphorus atom of the
phosphoramidate moiety is another source of chirality. Although the
structures below do not specifically depict chirality at
phosphorus, the inventors recognize that stereochemical
configurations are possible such that in a staggered (or zig-zag)
line structure the oxo-substitutent projects towards the viewer
while the OR.sup.1 substitutent projects away from the viewer, and
vice versa, i.e., where the Cahn-Ingold-Prelog stereochemical
designation of phosphorous is either R or S. Therefore, the
structures below include all possible stereochemical configurations
possible for phosphorus.
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Dosage, Administration, and Use
[0800] A sixth embodiment of the present invention is directed to a
composition for the treatment of any of the viral agents disclosed
herein said composition comprising a pharmaceutically acceptable
medium selected from among an excipient, carrier, diluent, and
equivalent medium and a compound, that is intended to include its
salts (acid or basic addition salts), hydrates, solvates, and
crystalline forms can be obtained, represented by formula I.
[0801] It is contemplated that the formulation of the sixth
embodiment can contain any of the compounds contemplated in any of
the aspects of the first, second, third, fourth, and fifth
embodiments or those specifically recited in the tables above or
exemplified herein, either alone or in combination with another
compound of the present invention.
[0802] The compounds of the present invention may be formulated in
a wide variety of oral administration dosage forms and carriers.
Oral administration can be in the form of tablets, coated tablets,
hard and soft gelatin capsules, solutions, emulsions, syrups, or
suspensions. Compounds of the present invention are efficacious
when administered by suppository administration, among other routes
of administration. The most convenient manner of administration is
generally oral using a convenient daily dosing regimen which can be
adjusted according to the severity of the disease and the patient's
response to the antiviral medication.
[0803] A compound or compounds of the present invention, as well as
their pharmaceutically acceptable salts, together with one or more
conventional excipients, carriers, or diluents, may be placed into
the form of pharmaceutical compositions and unit dosages. The
pharmaceutical compositions and unit dosage forms may be comprised
of conventional ingredients in conventional proportions, with or
without additional active compounds and the unit dosage forms may
contain any suitable effective amount of the active ingredient
commensurate with the intended daily dosage range to be employed.
The pharmaceutical compositions may be employed as solids, such as
tablets or filled capsules, semisolids, powders, sustained release
formulations, or liquids such as suspensions, emulsions, or filled
capsules for oral use; or in the form of suppositories for rectal
or vaginal administration. A typical preparation will contain from
about 5% to about 95% active compound or compounds (w/w). The term
"preparation" or "dosage form" is intended to include both solid
and liquid formulations of the active compound and one skilled in
the art will appreciate that an active ingredient can exist in
different preparations depending on the desired dose and
pharmacokinetic parameters.
[0804] The term "excipient" as used herein refers to a compound
that is used to prepare a pharmaceutical composition, and is
generally safe, non-toxic and neither biologically nor otherwise
undesirable, and includes excipients that are acceptable for
veterinary use as well as human pharmaceutical use. The compounds
of this invention can be administered alone but will generally be
administered in admixture with one or more suitable pharmaceutical
excipients, diluents or carriers selected with regard to the
intended route of administration and standard pharmaceutical
practice.
[0805] A "pharmaceutically acceptable salt" form of an active
ingredient may also initially confer a desirable pharmacokinetic
property on the active ingredient which were absent in the non-salt
form, and may even positively affect the pharmacodynamics of the
active ingredient with respect to its therapeutic activity in the
body. The phrase "pharmaceutically acceptable salt" of a compound
as used herein means a salt that is pharmaceutically acceptable and
that possesses the desired pharmacological activity of the parent
compound. Such salts include: (1) acid addition salts, formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with organic acids such as glycolic acid, pyruvic acid,
lactic acid, malonic acid, malic acid, maleic acid, fumaric acid,
tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic
acid, muconic acid, and the like or (2) basic addition salts formed
with the conjugate bases of any of the inorganic acids listed
above, wherein the conjugate bases comprise a cationic component
selected from among Na.sup.+, K.sup.+, Mg.sup.2+, Ca.sup.2+, and
NH.sub.gR''.sub.4-g.sup.+, in which R'' is a C.sub.1-3 alkyl and g
is a number selected from among 0, 1, 2, 3, or 4. It should be
understood that all references to pharmaceutically acceptable salts
include solvent addition forms (solvates) or crystal forms
(polymorphs) as defined herein, of the same acid addition salt.
[0806] Solid form preparations include powders, tablets, pills,
capsules, suppositories, and dispersible granules. A solid carrier
may be one or more substances which may also act as diluents,
flavoring agents, solubilizers, lubricants, suspending agents,
binders, preservatives, tablet disintegrating agents, or an
encapsulating material. In powders, the carrier generally is a
finely divided solid which is a mixture with the finely divided
active component. In tablets, the active component generally is
mixed with the carrier having the necessary binding capacity in
suitable proportions and compacted in the shape and size desired.
Suitable carriers include but are not limited to magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. Solid form preparations may contain, in addition to the
active component, colorants, flavors, stabilizers, buffers,
artificial and natural sweeteners, dispersants, thickeners,
solubilizing agents, and the like.
[0807] Liquid formulations also are suitable for oral
administration include liquid formulation including emulsions,
syrups, elixirs and aqueous suspensions. These include solid form
preparations which are intended to be converted to liquid form
preparations shortly before use. Emulsions may be prepared in
solutions, for example, in aqueous propylene glycol solutions or
may contain emulsifying agents such as lecithin, sorbitan
monooleate, or acacia. Aqueous suspensions can be prepared by
dispersing the finely divided active component in water with
viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other well
known suspending agents.
[0808] The compounds of the present invention may be formulated for
administration as suppositories. A low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter is first melted
and the active component is dispersed homogeneously, for example,
by stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool, and to solidify.
[0809] The compounds of the present invention may be formulated for
vaginal administration. Pessaries, tampons, creams, gels, pastes,
foams or sprays containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0810] Suitable formulations along with pharmaceutical carriers,
diluents and expcipients are described in Remington: The Science
and Practice of Pharmacy 1995, edited by E. W. Martin, Mack
Publishing Company, 19th edition, Easton, Pa., which is hereby
incorporated by reference. The compounds of the present invention
can also be encapsulated in liposomes, such as those disclosed in
U.S. Pat. Nos. 6,180,134, 5,192,549, 5,376,380, 6,060,080,
6,132,763, each of which is incorporated by reference. A skilled
formulation scientist may modify the formulations within the
teachings of the specification to provide numerous formulations for
a particular route of administration without rendering the
compositions of the present invention unstable or compromising
their therapeutic activity.
[0811] The modification of the present compounds to render them
more soluble in water or other vehicle, for example, may be easily
accomplished by minor modifications (e.g., salt formulation), which
are well within the ordinary skill in the art. It is also well
within the ordinary skill of the art to modify the route of
administration and dosage regimen of a particular compound in order
to manage the pharmacokinetics of the present compounds for maximum
beneficial effect in patients.
[0812] A seventh embodiment of the present invention is directed to
a use of the compound represented by formula I in the manufacture
of a medicament for the treatment of any condition the result of an
infection by any one of the following viral agents: hepatitis C
virus, West Nile virus, yellow fever virus, dengue virus,
rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea
virus and Japanese encephalitis virus.
[0813] The term "medicament" means a substance used in a method of
treatment and/or prophylaxis of a subject in need thereof, wherein
the substance includes, but is not limited to, a composition, a
formulation, a dosage form, and the like, comprising the compound
of formula I. It is contemplated that the compound of the use of
the compound represented by formula I in the manufacture of a
medicament for the treatment of any of the antiviral conditions
disclosed herein of the seventh embodiment can be any of the
compounds contemplated in any of the aspects of the first, second,
third, fourth, fifth embodiments or those specifically recited in
the tables above or exemplified herein, either alone or in
combination with another compound of the present invention. A
medicament includes, but is not limited to, any one of the
compositions contemplated by the sixth embodiment of the present
invention.
[0814] A eighth embodiment of the present invention is directed to
a method of treatment and/or prophylaxis in a subject in need
thereof said method comprises administering a therapeutically
effective amount of the compound represented by formula I to the
subject.
[0815] A first aspect of the eighth embodiment is directed to a
method of treatment and/or prophylaxis in a subject in need thereof
said method comprises administering a therapeutically effective of
at least two or more different compounds falling within the scope
of the compound represented by formula I to the subject.
[0816] A second aspect of the eighth embodiment is directed to a
method of treatment and/or prophylaxis in a subject in need thereof
said method comprises alternatively or concurrently administering a
therapeutically effective of at least two compounds falling within
the scope of the compound represented by formula I to the
subject.
[0817] It is intended that a subject in need thereof is one that
has any condition the result of an infection by any of the viral
agents disclosed herein, which includes, but is not limited to,
hepatitis C virus, West Nile virus, yellow fever virus, dengue
virus, rhinovirus, polio virus, hepatitis A virus, bovine viral
diarrhea virus or Japanese encephalitis virus, flaviviridae viruses
or pestiviruses or hepaciviruses or a viral agent causing symptoms
equivalent or comparable to any of the above-listed viruses.
[0818] The term "subject" means a mammal, which includes, but is
not limited to, cattle, pigs, sheep, chicken, turkey, buffalo,
llama, ostrich, dogs, cats, and humans, preferably the subject is a
human. It is contemplated that in the method of treating a subject
thereof of the sixth embodiment can be any of the compounds
contemplated in any of the aspects of the first, second, and third
embodiments or those specifically recited in the tables above,
either alone or in combination with another compound of the present
invention.
[0819] The term "therapeutically effective amount" as used herein
means an amount required to reduce symptoms of the disease in an
individual. The dose will be adjusted to the individual
requirements in each particular case. That dosage can vary within
wide limits depending upon numerous factors such as the severity of
the disease to be treated, the age and general health condition of
the patient, other medicaments with which the patient is being
treated, the route and form of administration and the preferences
and experience of the medical practitioner involved. For oral
administration, a daily dosage of between about 0.1 and about 10 g,
including all values in between, such as 0.25, 0.5, 0.75, 1, 1.5,
2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, and 9.5,
per day should be appropriate in monotherapy and/or in combination
therapy. A preferred daily dosage is between about 0.5 and about
7.5 g per day, more preferred 1.5 and about 6.0 g per day.
Generally, treatment is initiated with a large initial "loading
dose" to rapidly reduce or eliminate the virus following by a
decreasing the dose to a level sufficient to prevent resurgence of
the infection. One of ordinary skill in treating diseases described
herein will be able, without undue experimentation and in reliance
on personal knowledge, experience and the disclosures of this
application, to ascertain a therapeutically effective amount of the
compounds of the present invention for a given disease and
patient.
[0820] Therapeutic efficacy can be ascertained from tests of liver
function including, but not limited to protein levels such as serum
proteins (e.g., albumin, clotting factors, alkaline phosphatase,
aminotransferases (e.g., alanine transaminase, aspartate
transaminase), 5'-nucleosidase, .gamma.-glutaminyltranspeptidase,
etc.), synthesis of bilirubin, synthesis of cholesterol, and
synthesis of bile acids; a liver metabolic function, including, but
not limited to, carbohydrate metabolism, amino acid and ammonia
metabolism. Alternatively the therapeutic effectiveness may be
monitored by measuring HCV-RNA. The results of these tests will
allow the dose to be optimized.
[0821] A third aspect of the eighth embodiment, is directed to a
method of treatment and/or prophylaxis in a subject in need thereof
said method comprises administering to the subject a
therapeutically effective of a compound represented by formula I
and a therapeutically effective amount of another antiviral agent;
wherein the administration is concurrent or alternative. It is
understood that the time between alternative administration can
range between 1-24 hours, which includes any sub-range in between
including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, and 23 hours. Examples of "another antiviral
agents" include, but are not limited to: HCV NS3 protease
inhibitors (see WO 2008010921, WO 2008010921, EP 1881001, WO
2007015824, WO 2007014925, WO 2007014926, WO 2007014921, WO
2007014920, WO 2007014922, US 2005267018, WO 2005095403, WO
2005037214, WO 2004094452, US 2003187018, WO 200364456, WO
2005028502, and WO 2003006490); HCV NS5B Inhibitors (see US
2007275947, US20072759300, WO2007095269, WO 2007092000, WO
2007076034, WO 200702602, US 2005-98125, WO 2006093801, US
2006166964, WO 2006065590, WO 2006065335, US 2006040927, US
2006040890, WO 2006020082, WO 2006012078, WO 2005123087, US
2005154056, US 2004229840, WO 2004065367, WO 2004003138, WO
2004002977, WO 2004002944, WO 2004002940, WO 2004000858, WO
2003105770, WO 2003010141, WO 2002057425, WO 2002057287, WO
2005021568, WO 2004041201, US 20060293306, US 20060194749, US
20060241064, U.S. Pat. No. 6,784,166, WO 2007088148, WO 2007039142,
WO 2005103045, WO 2007039145, WO 2004096210, and WO 2003037895);
HCV NS4 Inhibitors (see WO 2007070556 and WO 2005067900); HCV NS5a
Inhibitors (see US 2006276511, WO 2006120252, WO 2006120251, WO
2006100310, WO 2006035061); Toll-like receptor agonists (see WO
2007093901); and other inhibitors (see WO 2004035571, WO
2004014852, WO 2004014313, WO 2004009020, WO 2003101993, WO
2000006529).
[0822] A fourth aspect of the eighth embodiment, is directed to a
method of treatment in a subject in need thereof said method
comprises alternatively or concurrently administering a
therapeutically effective of a compound represented by formula I
and another antiviral agent to the subject. It is understood that
the time between alternative administration can range between 1-24
hours, which includes any sub-range in between including, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
and 23 hours.
[0823] A fifth aspect of the eighth embodiment, is directed to a
method of treatment and/or prophylaxis in a subject in need thereof
said method comprises administering to the subject a
therapeutically effective of at least one compound represented by
formula I and a therapeutically effective amount of another
antiviral agent; wherein the administration is concurrent or
alternative. It is understood that the time between alternative
administration can range between 1-24 hours, which includes any
sub-range in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours.
[0824] A sixth aspect of the eighth embodiment, is directed to a
method of treatment in a subject in need thereof said method
comprises alternatively or concurrently administering a
therapeutically effective of at least one compound represented by
formula I and another antiviral agent to the subject. It is
understood that the time between alternative administration can
range between 1-24 hours, which includes any sub-range in between
including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, and 23 hours.
[0825] It is contemplated that the another antiviral agent
includes, but is not limited to interferon-.alpha.,
interferon-.beta., pegylated interferon-.alpha., ribavirin,
levovirin, viramidine, another nucleoside HCV polymerase inhibitor,
a HCV non-nucleoside polymerase inhibitor, a HCV protease
inhibitor, a HCV helicase inhibitor or a HCV fusion inhibitor. When
the active compound or its derivative or salt are administered in
combination with another antiviral agent the activity may be
increased over the parent compound. When the treatment is
combination therapy, such administration may be concurrent or
sequential with respect to that of the nucleoside derivatives.
"Concurrent administration" as used herein thus includes
administration of the agents at the same time or at different
times. Administration of two or more agents at the same time can be
achieved by a single formulation containing two or more active
ingredients or by substantially simultaneous administration of two
or more dosage forms with a single active agent.
[0826] It will be understood that references herein to treatment
extend to prophylaxis as well as to the treatment of existing
conditions. Furthermore, the term "treatment" of a HCV infection,
as used herein, also includes treatment or prophylaxis of a disease
or a condition associated with or mediated by HCV infection, or the
clinical symptoms thereof.
Process for Preparation
[0827] An ninth embodiment of the present invention is directed to
a process for preparing the compound of formula I, which comprises
reacting a suitably substituted phosphochloridate compound 4 with a
nucleoside analog 5
##STR00017##
[0828] wherein the substituents R.sup.1, R.sup.2, R.sup.3a,
R.sup.3b, R.sup.4, R.sup.5, X, Y, R.sup.6, and base have their
meanings as disclosed in the Detailed Description of the Invention
and X' is a leaving group, such as Cl, Br, I, tosylate, mesylate,
trifluoroacetate, trifluorosulfonate, pentafluorophenoxide,
p-NO.sub.2-phenoxide, or other commonly used leaving groups as
disclosed in Advanced Organic Chemistry by March, Fourth Edition.
Leaving groups and methods that can be used to effect the formation
of a phosphoramidate nucleoside conjugate are found in US
20060142238 and WO 2007095269. Preferably, the leaving group is
Cl.
[0829] This reaction is performed in an anhydrous aprotic solvent
such tetrahydrofuran, dioxane, or both tetrahydrofuran and dioxane,
or any functional equivalent thereof, with tetrahydrofuran being
the preferred solvent. The reaction is typically initiated at a
temperature range from -78.degree. C. to 40.degree. C. with the
preferred reaction temperature being between 0.degree. C. and room
temperature. The nucleoside is first stirred with a base (5 to 12
equivalents) such as N-methylimidazole, collidine, pyridine,
2,6-lutidine, 2, 6-.sup.tBu-pyridine, etc. a tertiary amine base,
such as triethylamine, diisopropylethylamine, etc., or an alkyl
Grignard reagent, such as tBuMgCl, tBuMgBr, MeMgCl, MeMgBr, etc.
The phosphorochloridate (3-10 equivalents) is dissolved in the
reaction solvent and added to the mixture of the nucleoside and
base. The reaction is then allowed to stir over a period of time at
a temperature between room temperature and 40.degree. C. for a
period of 30 min to 24 hr. with the preferred reaction temperature
being room temperature and time being 24 hr. The solvent is removed
from the reaction mixture and the product is purified by
chromatography on silica gel.
[0830] A tenth embodiment of the present invention is directed to a
product obtained by a process which comprises reacting a suitably
substituted phosphochloridate compound 4 with a nucleoside analog
5
##STR00018##
[0831] wherein the substituents R.sup.1, R.sup.2, R.sup.3a,
R.sup.3b, R.sup.4, R.sup.5, X, Y, R.sup.6, X', and base have their
meanings as disclosed in the Detailed Description of the
Invention.
[0832] This reaction can be performed in an anhydrous aprotic
solvent or other suitable solvent, such as tetrahydrofuran,
dioxane, or a mixture of tetrahydrofuran and dioxane, with
tetrahydrofuran being the preferred solvent. The reaction is
typically initiated at a temperature range from -78.degree. C. to
40.degree. C. with the preferred reaction temperature being between
0.degree. C. and room temperature. The nucleoside is first stirred
with a base (5 to 12 equivalents) such as N-methylimidazole, a
tertiary amine base or tButyl Magnesium Chloride. A
phosphorochloridate (3-10 equivalents (or suitable
"phosphoro-(leaving group)-date")) is dissolved in the reaction
solvent and added to the mixture of the nucleoside and base. The
reaction is then allowed to stir over a period of time at a
temperature between room temperature and 40.degree. C. for a period
of 30 min to 24 hr. with the preferred reaction temperature being
room temperature and time being 24 hr. The solvent is removed from
the reaction mixture and the product is purified by chromatography
on silica gel.
Compounds and Preparation
[0833] Phosphoramidate compounds of the present invention can be
prepared by condensation of a nucleoside analog 5 with a suitably
substituted phosphochloridate compound 4 (Scheme 1). The nucleoside
analog is made by conventional procedures disclosed in any one of
U.S. Published Application Nos. 2005/0009737, 2006/0199783,
2006/0122146, and 2007/0197463, each of which is incorporated by
reference in its entirety.
[0834] Disclosed 1H-NMR values were recorded on a Varian AS-400
instrument. Mass spectral data were obtain using either a
Micromass-Quattromicro API or a Waters Acquity.
[0835] Thus, by way of example only, a suitably substituted phenol
can be reacted with phosphorus oxychloride (1) to afford an aryloxy
phosphorodichloridate 2 (see Example 1) which is subsequently
treated with a acid addition salt of an a-amino acid ester in the
presence of TEA to afford an aryloxy phosphorochloridate 4. This
arylalkoxy-amino acid phosphoramidate is reacted with the
nucleoside analog to provide the product I (for procedure see,
e.g., C. McGuigan et al. Antiviral Res. 1992 17:311-321; D. Curley
et al. Antiviral Res. 1990 14:345-356; McGuigan et al. Antiviral
Chem. Chemother 1990 1(2):107-113).
##STR00019##
[0836] The preparation of nucleoside phosphoramidates requires
reacting an appropriately substituted phosphochloridate with a
nucleoside containing a free 5'-hydroxyl moiety. In cases where
only one hydroxyl group is present, preparation of the
phosphoramidate usually proceeds smoothly when the
phosphochloridate is reacted with the desired nucleoside. In cases
where the nucleoside contains more than one free hydroxyl group,
preparation of the appropriately protected nucleoside might be
required. Silyl, acetonide or other alcohol protecting groups known
in the art might be warranted for protection of the sugar moiety.
For protection of the nucleoside base, protecting a free amino
group may require amidine protection strategy.
[0837] Condensation of the phosphochloridate can be carried out on
the unprotected nucleoside. Since the 5'-OH group of a nucleoside
is much less hindered than the 3'-OH group, selective
phosphoramidation is possible under carefully controlled
conditions. After condensation to form a protected phosphoramidate
nucleoside, deprotection to obtain the free phosphoramidate
nucleoside can be carried out using standard protocols for nucleic
acid chemistry. In many cases, the desired product is readily
separated from the starting material using column chromatography on
silica gel. The synthetic scheme is summarized in Scheme 1.
[0838] A further understanding of the disclosed embodiments will be
appreciated by consideration of the following examples, which are
only meant to be illustrative, and not limit the disclosed
invention.
Example 1
General Procedure for Preparation of Phosphorodichloridates
##STR00020##
[0840] A solution of the appropriate phenol R.sup.1--OH (1 eq) and
triethylamine (1 eq.) in anhydrous ether was added dropwise to a
stirred solution of phosphoryl trichloride 1 (1 eq) at 0.degree. C.
over a period of 3 hours under nitrogen. Then the temperature was
warmed to room temperature, and the reaction was stirred overnight.
The triethylamine salt was quickly removed with suction filtration
and the filtrate concentrated in vacuo to dryness to afford 2 as an
oil which was used without further purification.
Example 2
General Procedure for Preparation of Phosphorochloridates
##STR00021##
[0842] A solution of triethylamine (2 eq) in anhydrous
dichloromethane was added dropwise to a solution of
aryloxy-phosphodichloridate 2 (1 eq) and the appropriate amino
ester 3 (1 eq) in anhydrous dichloromethane with vigorous stirring
at -78.degree. C. over a period of 30 to 120 minutes. Then the
reaction temperature was allowed to warm to room temperature and
stirred over night. Solvent was removed. The residue was washed
with ethyl ether and filtered, the filtrate was dried over reduced
pressure to give 4.
Example 3
General Procedures for Nucleoside Phosphoramidate Derivatives
##STR00022##
[0844] A solution of the appropriate phosphorochloridate 4 (6.5
equivalents) in anhydrous tetrahydrofuran (THF) was added to a
mixture of nucleoside 5 (1 equivalent) and N-methylimidazole (8
equivalents) in anhydrous THF with vigorous stirring at room
temperature and the reaction mixture was stirred overnight. The
solvent was removed in vacuo and the crude was purified by column
chromatography and/or preparative thin layer chromatography to give
I.
Example 4
Preparation of 2'-deoxy-2'-fluoro-2'-C-methyluridine
##STR00023##
[0846] 2'-Deoxy-2'-fluoro-2'-C-methylcytidine (1.0 g, 1 eq) (Clark,
J., et al., J. Med. Chem., 2005, 48, 5504-5508) was dissolved in 10
ml of anhydrous pyridine and concentrated to dryness in vacuo. The
resulting syrup was dissolved in 20 ml of anhydrous pyridine under
nitrogen and cooled to 0.degree. C. with stirring. The brown
solution was treated with benzoyl chloride (1-63 g, 3 eq) dropwise
over 10 min. The ice bath was removed and stirring continued for
1.5h whereby thin-layer chromatography (TLC) showed no remaining
starting material. The mixture was quenched by addition of water
(0.5 ml) and concentrated to dryness. The residue was dissolved in
50 mL of dichloromethane (DCM) and washed with saturated
NaHCO.sub.3 aqueous solution and H.sub.2O. The organic phase was
dried over NaSO.sub.4 and filtered, concentrated to dryness to give
N.sup.4,3',5'-tribenzoyl-2'-Deoxy-2'-fluoro-2'-C-methylcytidine
(2.0 g, Yield: 91%).
[0847]
N.sup.4,3',5'-tribenzoyl-2'-Deoxy-2'-fluoro-2'-C-methylcytidine
(2.0 g, 1 eq) was refluxed in 80% aqueous AcOH overnight. After
cooling and standing at room temperature (15.degree. C.), most of
the product precipitated and then was filtered through a sintered
funnel. White precipitate was washed with water and co-evaporated
with toluene to give a white solid. The filtrate was concentrated
and co-evaporated with toluene to give additional product which was
washed with water to give a white solid. Combining the two batches
of white solid gave 1.50 g of
3',5'-dibenzoyl-2'-Deoxy-2'-fluoro-2'-C-methyluridine (Yield:
91%).
[0848] To a solution of
3',5'-dibenzoyl-2'-Deoxy-2'-fluoro-2'-C-methyluridine (1.5 g, 1 eq)
in MeOH (10 mL) was added a solution of saturated ammonia in MeOH
(20 mL). The reaction mixture was stirred at 0.degree. C. for 30
min, and then warmed to room temperature slowly. After the reaction
mixture was stirred for another 18 hours, the reaction mixture was
evaporated under reduced pressure to give the residue, which was
purified by column chromatography to afford pure compound
2'-deoxy-2'-fluoro-2'-C-methyluridine (500 mg, Yield: 60%).
Example 5
Preparation of 2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(phenyl
methoxy-alanyl phosphate)
##STR00024##
[0850] Phenyl methoxyalaninyl phosphorochloridate (1 g, 6.5 eq)
dissolved in 3 mL of THF was added to a mixture of
2'-Deoxy-2'-fluoro-2'-C-methyluridine (0.15 g, 1 eq) and
N-methylimidazole (0.3 g, 8 eq) in 3 mL THF with vigorous stirring
at room temperature, then the reaction was stirred overnight.
Solvent was removed by reduced pressure. The resulting crude
product was dissolved in methanol purified by prep-HPLC on a YMC
25.times.30.times.2 mm column using a water/acetonitrile gradient
elution mobile phase. The acetonitrile and water were removed under
reduced pressure to give the desired product (50.1 mg, 15.6%).
.sup.1H NMR (DMSO-d.sub.6) .delta. 1.20-1.27 (m, 6H), 3.58 (d,
J=16.0 Hz, 3H), 3.75-3.92 (m, 2H), 4.015-4.379 (m, 2H), 5.54 (t,
J=10.2 Hz, 1H), 5.83-5.91 (m, 1H), 6.00-6.16 (m, 1H), 7.18 (d,
J=8.0 Hz, 2H), 7.22 (s, 1H), 7.35 (t, J=4.4 Hz, 2H), 7.55 (s, 1H),
11.52 (s, 1H); MS, m/e 502 (M+1).sup.+.
Example 6
Preparation of 2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(phenyl
methoxy-valyl phosphate)
##STR00025##
[0852] Phenyl methoxy-valyl phosphorochloridate (0.6 g, 3.6 eq)
dissolved in 3 mL of THF was added to a mixture of
2'-Deoxy-2'-fluoro-2'-C-methyluridine (0.15 g, 1 eq) and
N-methylimidazole (0.44 g, 9 eq) in 3 mL THF with vigorous stirring
at room temperature, then the reaction was stirred overnight.
Solvent was removed by reduced pressure. The resulting crude
product was dissolved in methanol purified by prep-HPLC on a YMC
25.times.30.times.2 mm column using a water/acetonitrile gradient
elution mobile phase. The acetonitrile and water were removed under
reduced pressure to give the desired product (60 mg, 20%). .sup.1H
NMR (DMSO-d.sub.6) .delta. 0.74-0.847 (m, 6H), 1.20-1.28 (m, 3H),
1.89-1.92 (m, 1H), 3.50-3.54 (m, 1H), 3.58 (d, J=10.4 Hz, 3H),
3.72-3.95 (m, 1H), 4.03-4.05 (m, 1H), 4.23-4.43 (m, 2H), 5.56 (t,
J=16.0 Hz, 1H), 5.85-5.92 (m, 1H), 6.01-6.07 (m, 1H), 7.16-7.21 (m,
3H), 7.37 (t, J=8 Hz, 2H), 7.55-7.60 (m, 1H), 11.52 (s, 1H); MS,
m/e 530 (M+1).sup.+.
Example 7
Preparation of 2'-Deoxy-2'-fluoro-2'-C-methyluridine
5'-(4-bromophenyl methoxy-valyl phosphate)
##STR00026##
[0854] 4-Bromophenyl methoxy-valyl phosphorochloridate (1 g, 3.4
eq) dissolved in 3 mL of THF was added to a mixture of
2'-deoxy-2'-fluoro-2'-C-methyluridine (0.2 g, 1 eq) and
N-methylimidazole (0.35 g, 6 eq) in 3 mL THF with vigorous stirring
at room temperature, then the reaction was stirred overnight.
Solvent was removed by reduced pressure. The resulting crude
product was dissolved in methanol purified by prep-HPLC on a YMC
25.times.30.times.2 mm column using a water/acetonitrile gradient
elution mobile phase. The acetonitrile and water were removed
reduced pressure to give the desired product (120 mg, 26%). .sup.1H
NMR (DMSO-d.sub.6) .delta. 0.72-0.82 (m, 6H), 1.19-1.26 (m, 3H),
1.86-1.92 (m, 1H), 3.48-3.50 (m, 1H), 3.56 (d, J=12.0 Hz, 3H),
3.72-3.89 (m, 1H), 3.96-4.03 (m, 1H), 4.22-4.37 (m, 2H), 5.54-5.60
(m, 1H), 5.85-5.91 (m, 1H), 5.98-6.13 (m, 1H), 7.15 (d, J=8.0 Hz,
2H), 7.49-7.56 (m, 3H), 11.53 (s, 1H); MS, m/e 608 (M+1).sup.+.
Example 8
Preparation of 2'-Deoxy-2'-fluoro-2'-C-methyluridine
5'-(4-bromophenyl methoxy-alanyl phosphate)
##STR00027##
[0856] 4-Bromophenyl methoxy-alanyl phosphorochloridate (0.6 g, 5
eq) dissolved in 3 mL of THF was added to a mixture of
2'-deoxy-2'-fluoro-2'-C-methyluridine (0.15 g, 1 eq) and
N-methylimidazole (0.3 g, 7.8 eq) in 3 mL THF with vigorous
stirring at room temperature, then the reaction was stirred
overnight. Solvent was removed by reduced pressure. The resulting
crude product was dissolved in methanol purified by prep-HPLC on a
YMC 25.times.30.times.2 mm column using a water/acetonitrile
gradient elution mobile phase. The acetonitrile and water were
removed under reduced pressure to give the desired product (40 mg,
12%); .sup.1H NMR (DMSO-d.sub.6) .delta. 1.20-1.26 (m, 6H), 3.57
(d, J=2.8 Hz, 3H), 3.84 (s, 1H), 3.97-4.03 (m, 1H), 4.21-4.25 (m,
1H), 4.33-4.37 (m, 2H), 5.54-5.60 (m, 1H), 5.83-5.89 (m, 1H),
5.98-6.19 (m, 1H), 7.16 (t, J=10.2 Hz, 2H), 7.52-7.57 (m, 3H),
11.52 (s, 1H); MS, m/e 580(M+1).sup.+.
Example 9
Preparation of
N.sup.4-(N,N-dimethylformamidinyl)-2'-deoxy-2'-fluoro-2'-C-methylcytidine
##STR00028##
[0858] 2'-Deoxy-2'-fluoro-2'-C-methylcytidine (500 mg, 1.9 mmol)
was stirred with dimethylformamide dimethyl acetal in DMF (10 mL).
The resulting mixture was stirred at room temperature overnight.
After solvent removal the crude product was used for next step
without further purification.
Example 10
Preparation of 2'-Deoxy-2'-fluoro-2'-C-methylcytidine 5'-(phenyl
methoxy-alanyl phosphate)
##STR00029##
[0860] Phenyl methoxyalaninyl phosphorochloridate (0.6 g, 6 eq)
dissolved in 3 mL of THF was added to a mixture of
N.sup.4-(N,N-dimethylformamidinyl)-2'-deoxy-2'-fluoro-2'-C-methylcytidine
(0.15 g, 1 eq) and N-methylimidazole (0.3 g, 7.8 eq) in 3 mL THF
with vigorous stirring at room temperature, then the reaction was
stirred overnight. Solvent was removed by reduced pressure. The
resulting crude product was dissolved in methanol purified by
prep-HPLC on a YMC 25.times.30.times.2 mm column using a
water/acetonitrile gradient elution mobile phase. The acetonitrile
and water were removed under reduced pressure to give the desired
product (62 mg, 20.6%). .sup.1H NMR (DMSO-d.sub.6) .delta. 1.16 (d,
J=23.2 Hz, 3H), 1.22 (d, J=7.2 Hz, 3H), 3.56 (S, 3H), 3.69-3.75 (d,
J=25.6 Hz, 1H), 3.82-3.86 (m, 1H), 3.96-3.98 (m, 1H), 4.21-4.34 (m,
2H), 5.68 (d, J=7.2 Hz, 1H), 5.75-5.77 (m, 1H), 6.07-6.16 (m, 1H),
7.15-7.19 (m, 3H), 7.2 (d, J=9.2 Hz, 2H), 7.39 (t, J=7.8 Hz, 2H),
7.48 (d, J=9.2 Hz, 1H); MS, m/e 501(M+1).sup.+.
Example 11
Preparation of 2'-Deoxy-2'-fluoro-2'-C-methylcytidine
5'-(4-bromophenyl methoxy-valyl phosphate)
##STR00030##
[0862] 4-Bromophenyl methoxy-valyl phosphorochloridate (1.0 g, 3.4
eq.) dissolved in 3 mL of THF was added to a mixture of
N.sup.4-(N,N-dimethylformamidinyl)-2'-deoxy-2'-fluoro-2'-C-methylcytidine
(0.2 g, 1 eq.) and N-methylimidazole (0.35 g, 6 eq.) in 3 mL THF
with vigorous stirring at room temperature, then the reaction was
stirred overnight. Solvent was removed by reduced pressure. The
resulting crude product was dissolved in methanol purified by
prep-HPLC on a YMC 25.times.30.times.2 mm column using a
water/acetonitrile gradient elution mobile phase. The acetonitrile
and water were removed under reduced pressure to give the desired
product as a white solid (59 mg, 13%); .sup.1H NMR (DMSO-d.sub.6)
.delta. 0.74-0.83 (m, 6H), 1.12-1.20 (m, 3H), 1.89-1.92 (m, 1H),
3.49-3.51 (m, 1H), 3.55 (s, 3H), 3.59-3.68 (m, 1H), 3.72-3.83 (m,
1H), 4.21-4.39 (m, 2H), 5.70-5.72 (m, 1H), 5.76-5.83 (m, 1H),
6.04-6.16 (m, 1H), 7.15 (d, J=13.0 Hz, 2H), 7.26 (s, 1H), 7.33 (s,
1H), 7.46-7.55 (m, 1H), 7.56 (d, J=4.4 Hz, 2H); MS, m/e 607
(M+1).sup.+.
Example 12
Preparation of 2'-deoxy-2'-fluoro-2'-C-methylcytidine 5'-(phenyl
methoxy-valyl phosphate)
##STR00031##
[0864] Phenyl methoxy-valyl phosphorochloridate (0.6 g, 6 eq)
dissolved in 3 mL of THF was added to a mixture of
N.sup.4-(N,N-dimethylformamidinyl)-2'-deoxy-2'-fluoro-2'-C-methylcytidine
(0.15 g, 1 eq) and N-methylimidazole (0.3 g, 7.8 eq) in 3 mL THF
with vigorous stirring at room temperature, then the reaction was
stirred overnight. Solvent was removed by reduced pressure The
resulting crude product was dissolved in methanol purified by
prep-HPLC on a YMC 25.times.30.times.2 mm column using a
water/acetonitrile gradient elution mobile phase. The acetonitrile
and water were removed under reduced pressure to give the desired
product as a white solid (86 mg, 42.9%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 0.72-0.80 (m, 6H), 1.09-1.18 (m, 3H), 1.87-1.92 (m, 1H),
3.47-3.51 (m, 1H), 3.58 (s, 3H), 3.71-3.75 (m, 1H), 3.97 (t, J=11.2
Hz, 1H), 4.22-4.37 (m, 2H), 5.70 (d, J=8.0 Hz, 1H), 5.76-5.84 (m,
1H), 6.01-6.15 (m, 1H), 7.13-7.18 (m, 3H), 7.27 (s, 2H), 7.34 (d,
J=4.0 Hz, 2H), 7.46-7.50 (m, 1H); MS, m/e 529 (M+1).sup.+.
EXAMPLES
[0865] Example numbers 13-54 and 56-66 are prepared using similar
procedures described for examples 5-8. The example number, compound
identification, and NMR/MS details are shown below:
TABLE-US-00032 ##STR00032## Ex. R.sup.1 R.sup.2 R.sup.3a R.sup.3b
R.sup.4 NMR/MS 13 Ph H H Me Et 1H NMR (DMSO-d.sub.6) .delta.
1.12-1.16 (m, 3H), 1.20-1.28 (m, 6H), 3.70-3.90 (m, 2H), 4.00-4.08
(m, 3H), 4.18-4.45 (m, 2H), 5.52-5.58 (m, 1H), 5.85-5.98 (m, 1H),
6.00-6.20 (m, 2H), 7.16-7.23 (m, 3H), 7.37-7.40 (m, 2H), 7.54-7.60
(m, 1H), 11.54 (s, 1H); MS, m/e 516.1 (M + 1)+ 14 1-Napth H H Me Bn
1H NMR (DMSO-d.sub.6) .delta. 1.18-1.30 (m, 6H), 3.78-4.10 (m, 3H),
4.38- 4.49 (m, 2H), 4.99-5.11 (m, 2H), 5.28-5.40 (m, 1H), 5.85-6.10
(m, 2H), 6.30-6.41 (m, 1H), 7.28-7.32 (m, 5H), 7.41-7.60 (m, 5H),
7.73- 7.76 (m, 1H), 7.94-8.11 (m, 1H), 8.13-8.15 (m, 1H), 11.50 (s,
1H); MS, m/e 628.4 (M + 1)+ 15 Ph H H H Me 1H NMR (DMSO-d.sub.6)
.delta. 1.22 (d, J = 22.4 Hz, 3H), 3.59 (s, 3H), 3.63-3.69 (m, 2H),
3.74-3.8 (m, 1H), 4.02 (d, J = 11.2 Hz, 1H), 4.23-4.28 (m, 1H),
4.40-4.43 (m, 1H), 5.57-5.60 (m, 1H), 5.89 (d, J = 6.8 Hz, 1H),
6.00- 6.06 (m, 2H), 7.15-7.23 (m, 3H), 7.35-7.39 (m, 2H), 7.52 (d,
J = 8 Hz, 1H), 11.52 (s, 1H); MS, m/e 487.97 (M + 1)+ 16 2,4-Cl--Ph
H H Me Me 1H NMR (DMSO-d.sub.6) .delta. 1.22-1.28 (m, 6H),
3.57-3.60 (m, 3H), 3.84- 3.92 (m, 2H), 4.00-4.04 (m, 1H), 4.31-4.44
(m, 2H), 5.54-5.61 (m, 1H), 5.85-6.10 (m, 2H), 6.32-6.43 (m, 1H),
7.44-7.54 (m, 3H), 7.72- 7.75 (m, 1H), 11.54 (s, 1H); MS, m/e 570.2
(M + 1)+ 17 1-Napth H H Me Me 1H NMR (DMSO-d.sub.6) .delta.
1.15-1.27 (m, 6H), 3.51-3.55 (d, 3H), 3.85- 3.96 (m, 2H), 4.00-4.10
(m, 1H), 4.30-4.46 (m, 2H), 5.31-5.39 (m, 1H), 5.89-6.05 (m, 2H),
6.22-6.34 (m, 1H), 7.44-7.60 (m, 5H), 7.73-7.77 (m, 1H), 7.93-7.96
(m, 1H), 8.12-8.14 (m, 1H), 11.50 (s, 1H); MS, m/e 552.1 (M + 1)+
18 Ph * H * Me 1H NMR (DMSO-d.sub.6) .delta. 1.19 (d, J = 22.8 Hz,
3H), 1.69-1.84 (m, 3H), 1.99-2.04 (m, 1H), 3.16-3.21 (m, 2H), 3.58
(s, 3H), 3.68-3.8 (m, 1H), 4.00 (m, 1H), 4.01-4.13 (m, 1H),
4.22-4.25 (m, 1H), 4.5 (d, J = 11.2 Hz, 1H), 5.54 (d, J = 8.0 Hz,
1H), 5.86 (s, 1H), 5.6 (d, J = 19.6 Hz, 1H), 7.15-7.2 (m, 3H), 7.34
(t, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 11.38 (s, 1H); MS,
m/e 527.93 (M + 1)+ 19 Ph H H Me n-Bu 1H NMR (DMSO-d.sub.6) .delta.
0.80-0.90 (m, 3H), 1.20-1.35 (m, 8H), 1.48- 1.55 (m, 2H), 3.78-3.88
(m, 2H), 3.95-4.08 (m, 3H), 4.22-4.45 (m, 2H), 5.55-5.57 (t, 1H),
5.85-6.18 (m, 3H), 7.14-7.23 (m, 3H), 7.35-7.40 (m, 2H), 7.51-7.60
(d, 1H), 11.50 (s. 1H); MS, m/e 544.2 (M + 1)+ 20 Ph H H Me Bn 1H
NMR (DMSO-d.sub.6) .delta. 1.20-1.30 (m, 6H), 3.72-4.05 (m, 3H),
4.23- 4.27 (m, 1H), 4.32-4.45 (m, 1H), 5.07-5.10 (t, 2H), 5.52-5.56
(t, 1H), 5.86-6.10 (m, 2H), 6.13-6.21 (m, 1H), 7.15-7.21 (m, 3H),
7.29-7.40 (m, 7H), 7.51-7.56 (d, 1H), 11.50 (s, 1H); MS, m/e 578.2
(M + 1)+ 21 4-F--Ph H H Me Me 1H NMR (DMSO-d.sub.6) .delta.
1.28-1.34 (m, 6H), 3.65 (d, J = 4 Hz, 3H), 3.85- 3.96 (m, 2H),
4.06-4.12 (m, 1H), 4.30-4.34 (m, 1H), 4.40-4.47 (m, 1H), 5.62-5.67
(m, 1H), 5.94-6.01 (m, 1H), 6.09 (d, J = 18.8 Hz, 1H), 6.17- 6.26
(m, 1H), 7.27-7.33 (m, 4H), 7.62 (d, J = 7.6 Hz, 1H), 11.61 (s,
1H); MS, m/e 519.94 (M + 1)+ 22 4-Cl--Ph H H Me Me 1H NMR
(DMSO-d.sub.6) .delta. 1.22-1.28 (m, 6H), 3.58 (d, 2H), 3.70- 3.95
(m, 2H), 3.95-4.08 (m, 1H), 4.23-4.45 (m, 2H), 5.55-5.61 (t , 1H),
5.85-6.10 (m, 2H), 6.15-6.23 (m, 1H), 7.20-7.26 (m, 2H), 7.43-7.46
(m, 2H), 7.54-7.57 (d, 1H), 11.50 (s, 1H); MS, m/e 536.1 (M + 1)+
23 3,4-C1--Ph H H Me Me 1H NMR (DMSO-d.sub.6) .delta. 1.13 (m, 6H),
3.49 (s, 3H), 3.61-3.85 (m, 2H), 3.90-3.93 (m, 1H), 4.16-4.22 (m,
1H), 4.27-4.31 (m, 1H), 5.47-5.52 (m, 1H), 5.82 (d, J = 11.6 Hz,
1H), 5.93 (d, J = 19.2 Hz, 1H), 6.15-6.25 (m, 1H), 7.13 (t, J = 9.6
Hz, 1H), 7.43 (d, J = 12 Hz, 2H), 7.57 (d, J = 6.0 Hz, 1H), 11.43
(s, 1H); MS, m/e 569.85 (M + 1)+ 24 Ph H H Me 2-Bu 1H NMR
(DMSO-d.sub.6) .delta. 0.83 (d, J = 6.8 Hz, 6H), 1.20-1.26 (m, 6H),
1.79-1.86 (m, 1H), 3.73-3.90 (m, 4H), 4.01 (t, J = 11.2 Hz, 1H),
4.21- 4.28 (m, 1H), 4.33-4.42 (m, 1H), 5.54 (t, J = 7.6 Hz, 1H),
5.85-5.92 (m, 1H), 5.99-6.13 (m, 2H), 7.19 (t, J = 8 Hz, 3H), 7.36
(t, J = 7.6 Hz, 2H), 7.53 (d, J = 7.6 Hz, 1H), 11.52 (s, 1H); MS,
m/e 544.00 (M + 1)+ 25 Ph H H Me i-Pr 1H NMR (DMSO-d.sub.6) .delta.
1.13-1.28 (m, 12H), 3.74-3.81 (m, 2H), 3.95- 4.08 (m, 1H),
4.20-4.45 (m, 2H), 4.83-4.87 (m, 1H), 5.52-5.58 (m, 1H), 5.84-6.15
(m, 3H), 7.17-7.23 (m, 3H), 7.35-7.39 (m, 2H), 7.54-7.57 (m, 1H),
11.50 (s, 1H); MS, m/e 530.2 (M + 1)+ 26 4-MeO--Ph H H Me n-Bu 1H
NMR (400 MHz, DMSO-d.sub.6): .delta. = 0.78-0.82 (m, 3H), 1.29-1.47
(m, 8H), 1.49-1.54 (m, 2H), 3.66-3.87 (m, 5H), 3.96-4.02 (m, 3H),
4.21- 4.39 (m, 2H), 5.57 (t, J = 12.0 Hz, 1H), 5.84-6.05 (m, 3H),
6.90 (dd, J1 = 8.0 Hz, J2 = 4.0 Hz, 2H), 7.09-7.14 (dd, J1 = 16.0
Hz, J2 = 4.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H), 11.48-11.62 (s, 1H)
27 4-F--Ph H H Me Et 1H NMR (DMSO-d.sub.6) .delta. 1.12-1.28 (m,
9H), 3.72-3.94 (m, 2H), 3.98-4.10 (m, 3H), 4.21-4.42 (m, 2H),
5.55-5.61 (t, 1H), 5.85-6.20 (m, 3H), 7.18- 7.25 (m, 4H), 7.55-7.58
(d, 1H), 11.50 (s, 1H); MS, m/e 533.90 (M + 1)+ 28 4-F--Ph H H Me
i-Pr 1H NMR (DMSO-d.sub.6) .delta. 1.13-1.30 (m, 12H), 3.74-3.85
(m, 2H), 3.98- 4.06 (m, 1H), 4.23-4.41 (m, 2H), 4.83-4.87 (m, 1H),
5.55-5.61 (t, 1H), 5.85-6.12 (m, 3H), 7.18-7.24 (m, 4H), 7.55-7.58
(d, 1H), 11.50 (s, 1H); MS, m/e 547.91 (M + 1)+ 29 4-F--Ph H H Me
Bn 1H NMR (DMSO-d.sub.6) .delta. 1.10-1.23 (m, 6H), 3.65-3.89 (m,
3H), 4.10-4.30 (m, 2H), 4.96-5.00 (m, 2H), 5.46-5.50 (t, 1H),
5.75-5.96 (m, 2H), 6.04- 6.12 (m, 1H), 7.05-7.11 (m, 4H), 7.20-7.24
(d, 5H), 7.42-7.45 (d, 1H), 11.50 (s, 1H); MS, m/e 595.94 (M + 1)+
30 4-MeO--Ph H H Me i-Pr 1H NMR (400 MHz, DMSO-d.sub.6): .delta. =
1.15-1.27 (m, 12H), 3.71-3.89 (m, 5H), 3.98-4.02 (m, 1H), 4.22-4.25
(m, 1H), 4.33-4.39 (m, 1H), 4.84- 4.87 (m, 1H), 5.57 (t, J = 12.0
Hz, 1H), 5.91-6.03 (m, 3H), 6.90 (d, J = 8.0 Hz, 2H), 7.09-7.14 (m,
2H), 7.55 (d, J = 8.0 Hz, 1H), 11.51 (s, 1H) 31 2-Cl--Ph H H Me Bn
1H NMR (DMSO-d.sub.6) .delta. 1.23 (m, 6 H), 3.93-4.00 (m, 3 H),
4.27-4.40 (m, 2H), 5.0 (t, J = 7.2 Hz, 2 H), 5.53 (m, 1 H),
5.80-6.0 (m, 2 H), 6.30 (m, 1H), 7.15 (d, J = 2.4 Hz, 1 H), 7.27
(m, 6 H), 7.51 (m, 3 H), 11.5 (s, 1 H); MS, m/e 579.87 (M + 1)+ /
596.78 (M + 18)+ 32 2,4-Cl--Ph H H Me n-Bu 1H NMR (DMSO-d.sub.6)
.delta. = 0.82 (m, 3 H), 1.23 (m, 8 H), 1.47 (m, 2 H), 3.86 (m, 2
H), 3.84 (m, 3 H), 4.27-4.43 (m, 2H), 5.5 (m, 1 H), 6.02 (m, 2 H),
6.35 (m, 1H), 7.44 (m, 3 H), 7.77 (m, 1 H), 11.5 (s, 1 H); MS, m/e
611.87 (M + 1)+ 33 4-Me--Ph H H Me i-Pr 1H NMR (DMSO-d.sub.6)
.delta. 1.14-1.27 (m, 12H), 2.17-2.26 (m, 3H), 3.73- 3.82 (m, 1H),
3.99-4.02 (m, 1H), 4.23-4.26 (m, 1H), 4.37-4.40 (m, 1H), 4.82-4.88
(m, 1H), 5.52-5.58 (m, 1H), 5.85-6.07 (m, 3H), 7.01- 7.20 (m, 4H),
7.55 (d, J = 16 Hz, 1H), 11.51 (s, 1H); MS, m/e 543.98 (M + 1)+;
1108.86 (2M + 23)+ 34 4-F--Ph H H Me n-Bu 1H NMR (DMSO-d.sub.6)
.delta. 0.82-0.89 (m, 3H), 1.20-1.31 (m, 8H), 1.48- 1.53 (m, 2H),
3.77-3.90 (m, 2H), 3.95-4.10 (m, 3H), 4.21-4.45 (m, 2H), 5.56-5.61
(t, 1H), 5.83-6.20 (m, 3H), 7.18-7.25 (m, 4H), 7.55-7.58 (d, 1H),
11.50 (s, 1H); MS, m/e 584.1 (M + 23)+ 35 3,4-diCl--Ph H H Me Et 1H
NMR (DMSO-d.sub.6) .delta. 1.12-1.31 (m, 9H), 3.77-3.92 (m, 2H),
3.95-4.08 (m, 3H), 4.21-4.45 (m, 2H), 5.56-5.62 (t, 1H), 5.80-6.11
(m, 2H), 6.18- 6.33 (m, 1H), 7.18-7.25 (m, 1H), 7.49-7.56 (d, 2H),
7.62-7.67 (m, 1H), 11.50 (s, 1H); MS, m/e 606.1 (M + 23)+ 36
2-Cl--Ph H H Me i-Pr 1H NMR (400 MHz, DMSO-d.sub.6): .delta. =
1.12-1.16 (m, 6H), 1.21-1.27 (m, 6H), 3.79-3.85 (m, 2H), 4.00-4.07
(m, 1H), 4.28-4.32 (m, 1H), 4.38- 4.43 (m, 1H), 4.83-4.87 (m, 1H),
5.56 (dd, J1 = 16.0 Hz, J2 = 8.0 Hz, 1H), 5.85-6.12 (m, 2H),
6.20-6.33 (m, 1H), 7.19-7.22 (m, 1H), 7.33 (t, J = 16.0 Hz, 1H),
7.48-7.55 (m, 3H), 11.55 (s, 1H) 37 4-MeO--Ph H H Me Bn 1H NMR (400
MHz, DMSO-d.sub.6): .delta. = 1.19-1.26 (m, 6H), 3.69-3.70 (s, 3H),
3.87 (m, 2H), 3.99 (m, 1H), 4.20-4.21 (m, 1H), 4.35 (m, 1H),
5.07-5.09 (m, 2H), 5.54 (t, J = 16.0 Hz, 1H), 5.85-5.92 (m, 1H),
6.04- 6.10 (m, 2H), 6.86 (d, J = 8.0 Hz, 2H), 7.09 (dd, J1 = 16.0
Hz, J2 = 4.0 Hz, 2H), 7.30-7.34 (m, 5H), 7.53 (s, 1H), 11.52 (s,
1H) 38 Ph H H Me n-Pen 1H NMR (DMSO-d.sub.6) .delta. 0.79-0.81 (m,
3H), 1.17-1.23 (m, 10H), 3.74- 3.81 (m, 2H), 3.94-3.96 (m, 3H),
4.19-4.36 (m, 2H), 5.49-5.54 (m, 1H), 5.87-6.08 (m, 3H), 7.14-7.33
(m, 3H), 7.31-7.35 (m, 2H), 7.51 (d, J = 8 Hz, 1H), 11.51 (s, 1H);
MS, m/e 557.9 (M + 1)+; 1136.88 (2M + 23)+ 39 4-Cl--Ph H H Me i-Pr
1H NMR (DMSO-d.sub.6) .delta. 1.04-1.19 (m, 12H), 3.76-3.80 (m,
2H), 3.98- 4.08 (m, 1H), 4.42-4.42 (m, 2H), 4.82-4.85 (m, 1H),
5.55-5.60 (m, 1H), 5.80-6.20 (m, 3H), 7.20-7.25 (m, 2H), 7.43 (d, J
= 8.8 Hz, 1H), 7.54 (d, J = 8 Hz, 1H), 11.51 (s, 1H); MS, m/e
563.88 (M + 1)+; 1148.73 (2M + 23)+ 40 4-Cl--Ph H H Me n-Bu 1H NMR
(DMSO-d.sub.6) .delta. 0.85 (t, J = 7.2 Hz, 3H), 1.22-1.33 (m, 8H),
1.45-1.53 (m, 2H), 3.80-3.87 (m, 2H), 3.96-4.04 (m, 3H), 4.24- 4.27
(m, 1H), 4.35-4.39 (m, 1H), 5.56-5.61 (m, 1H), 5.82-6.11 (m, 2H),
6.15-6.18 (m, 1H), 7.20-7.56 (m, 4H), 7.51-7.57 (m, 1H), 11.54 (s,
1H); MS, m/e 577.95 (M + 1)+ 41 4-Cl--Ph H H Me Et 1H NMR
(DMSO-d.sub.6) .delta. 1.14 (t, J = 7.0 Hz, 3H), 1.20-1.28 (m, 6H),
3.77-3.88 (m, 2H), 3.99-4.07 (m, 3H), 4.24-4.28 (m, 1H), 4.34- 4.43
(m, 1H), 5.56-5.61 (m, 1H), 5.86-6.13 (m, 2H), 6.15-6.24 (m, 1H),
7.20-7.26 (m, 2H), 7.44 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.6 Hz,
1H), 11.55 (s, 1H); MS, m/e 549.11 (M + 1)+ 42 4-Me--Ph H H Me n-Bu
1H NMR (DMSO-d.sub.6) .delta. 0.79-0.83 (m, 3H), 1.17-1.28 (m, 8H),
1.45- 1.47 (m, 2H), 2.22 (d, J = 2.8 Hz, 1H), 3.70-3.90 (m, 2H),
3.95-3.98 (m, 3H), 4.10-4.40 (m, 2H), 5.51 (t, 1H), 5.80-5.90 (m,
1H), 5.95-6.05 (m, 2H), 7.02-7.06 (m, 2H), 7.51 (t, J = 4.2 Hz,
4H), 7.51 (d, 1H), 11.51 (s, 1H); MS, m/e 557.99 (M + 1)+; 1136.84
(2M + 23)+ 43 4-Me--Phe H H Me Bn 1H NMR (DMSO-d.sub.6) .delta.
1.16-1.24 (m, 6H), 2.22 (s, 3H), 3.65-4.03 (m, 3H), 4.11-4.38 (m,
2H), 5.04-5.05 (m, 2H), 5.48-5.50 (m, 1H), 5.77-5.87 (m, 1H),
5.90-6.11 (m, 2H), 6.98-7.10 (m, 4H), 7.28-7.32 (m, 5H), 7.50 (t,
1H), 11.48 (s, 1H); MS, m/e 592.00 (M + 1)+. 44 Ph H H Et Me 1H NMR
(DMSO-d.sub.6) .delta. 0.70-0.80 (m, 3H), 1.11-1.26 (m, 3H), 1.42-
1.61 (m, 2H), 3.50-3.54 (m, 3H), 3.58-3.80 (m, 2H), 3.91-4.02 (m,
1H), 4.12-4.38 (m, 2H), 5.47-5.52 (m, 1H), 5.90-6.03 (m, 2H), 7.08-
7.16 (m, 3H), 7.26-7.35 (m, 2H), 7.48 (t, 1H), 11.45 (s, 1H); MS,
m/e 515.95 (M + 1)+; 1052.82 (2M + 23)+ 45 Ph H H Me 4-F--Bn
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.20-1.26 (m, 6H),
3.80-3.93 (m, 2H), 3.98 (s, 1H), 4.25-4.26 (m, 1H), 4.36-4.37 (m,
1H), 5.07 (s, 2H), 5.52-5.55 (m, 1H), 5.86-5.87 (m, 1H), 5.98-6.04
(m, 1H), 6.14-6.17 (m, 1H), 7.15-7.20 (m, 5H), 7.36 (dd, J = 20.0,
8.0 Hz, 4H), 7.54 (s, 1H), 11.55 (s, 1H) 46 4-Cl--Ph H H Me n-Bu
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.21-1.28 (m, 6H),
3.71-3.88 (m, 1H), 3.91-3.98 (m, 1H), 4.00-4.01 (m, 1H), 4.23-4.27
(m, 1H), 4.35- 4.38 (m, 1H), 5.08 (d, J = 4.0 Hz, 2H), 5.57 (dd, J
= 12.0, 8.0 Hz, 1H),
5.91 (d, J = 8.0 Hz, 1H), 6.01 (d, J = 8.0 Hz, 1H), 6.22-6.24 (m,
1H), 7.17-7.23 (m, 2H), 7.31-7.40 (m, 7H), 7.53 (s, 1H), 11.50 (s,
1H) 47 Ph H H Me 3-Me-1-Bu .sup.1H NMR (DMSO-d.sub.6) .delta.
0.80-0.82 (m, 6H), 1.18-1.40 (m, 8H), 1.50- 1.58 (m, 1H), 3.71-3.82
(m, 3H), 3.97-3.4.01 (m, 3H), 4.21-4.40 (m, 2H), 5.30 (t, J = 8.6
Hz, 1H), 5.81-6.10 (m, 3H), 7.15-7.20 (m, 3H), 7.32-7.36 (m, 2H),
7.48 (d, J = 8.4 Hz, 1H), 11.38 (s, 1H); MS, m/e 557.98 (M +
1).sup.+; 1136.88 (2M + 23).sup.+ 48 3,4-diCl--Ph H H Me Bn .sup.1H
NMR (DMSO-d.sub.6) .delta. 1.05-1.37 (m, 6H), 3.71-3.82 (m, 1H),
3.87- 4.02 (m, 2H), 4.28-4.29 (m, 1H), 4.36-4.38 (m, 1H), 5.04 (d,
J = 5.2 Hz, 2H), 5.55-5.64 (m, 1H), 5.85-5.94 (m, 1H), 6.00-6.05
(m, 1H), 6.29- 6.40 (m, 1H), 7.17-7.24 (m, 1H), 7.30-7.41 (m, 5H),
7.45-7.58 (m, 2H), 7.61 (d, J = 4.0 Hz, 1H), 11.53 (s, 1H); MS, m/e
545.80 (M + 1).sup.+; 49 Ph H H Me c-Hex .sup.1H NMR (DMSO-d.sub.6)
.delta. 1.18-1.41 (m, 12H), 1.59-1.67 (m, 4H), 3.74- 13.80 (m, 1H),
3.96-4.02 (m, 1H), 4.19-4.26 (m, 1H), 4.31-4.39 (m, 1H), 4.60 (s,
1H), 5.52 (t, J = 7.8 Hz, 1H), 5.80-6.09 (m, 3H), 7.15- 7.20 (m,
3H), 7.32-7.36 (m, 2H), 7.52 (d, J = 8 Hz, 1H), 11.50 (s, 1H); MS,
m/e 569.98 (M + 1).sup.+; 592.14 (M + 23).sup.+ 50 Ph H Me H n-Bu
1H NMR (DMSO-d.sub.6) .delta. 0.76 (t, J = 7.2 Hz, 3H), 1.10-1.22
(m, 8H), 1.38-1.43 (m, 2H), 3.72-3.75 (m, 2H), 3.87-3.93 (m, 3H),
4.14-4.21 (m, 1H), 4.23-4.33 (m, 1H), 5.46-5.54 (m, 1H), 5.84-6.11
(m, 3H), 7.09-7.14 (m, 2H), 7.27-7.32 (m, 2H), 7.34-7.51 (m, 1H),
11.47 (s, 1H); MS, m/e 543.98 (M + 1)+ 51 Ph H Me H i-Pr 1H NMR
(DMSO-d.sub.6) .delta. 1.39 (d, J = 7.2 Hz, 6H), 1.19-1.29 (m, 6H),
3.65-3.75 (m, 2H), 3.95-4.05 (m, 1H), 4.20-4.22 (m, 1H), 4.31-4.33
(m, 1H), 4.79-4.82 (m, 1H), 5.48-5.57 (m, 1H), 5.84-5.91 (m, 1H),
5.96-6.07 (m, 2H), 7.12-7.35 (m, 5H), 7.44-7.54 (m, 1H), 11.49 (s,
1H); MS, m/e 529.96 (M + 1)+ 52 Ph H Me H Bn .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.18-1.28 (m, 6H), 3.70-3.83 (m, 1H), 3.87-
3.94 (m, 1H), 3.99-4.01 (m, 1H), 4.23-4.26 (m, 1H), 4.33-4.37 (m,
1H), 5.03-5.12 (m, 2H), 5.51-5.59 (m, 1H), 5.87-5.90 (m, 1H), 5.95-
6.07 (m, 1H), 6.10-6.27 (m, 1H), 7.15-7.23 (m, 3H), 7.31-7.38 (m,
7H), 7.47-7.56 (m, 1H), 11.50 (s, 1H); MS, m/e 577.99 (M + 1)+ 53
2-Cl--Ph H H Me n-Bu .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
0.81-0.86 (m, 3H), 1.21-1.31 (m, 8H), 1.46-1.52 (m, 2H), 3.84-3.90
(m, 2H), 3.97-4.04 (m, 3H), 4.27- 4.41 (m, 2H), 5.53-5.58 (m, 1H),
5.82-5.95 (m, 1H), 5.96-6.10 (m, 1H), 6.27-6.31 (m, 1H), 7.19-7.22
(m, 1H), 7.34 (dd, J = 8.0, 4.0 Hz, 1H), 7.47-7.55 (m, 3H), 11.55
(s, 1H) 54 4-Br--Ph H H Me i-Pr .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.10-1.14 (m, 6H), 1.20-1.27 (m, 6H),
3.74-3.81 (m, 2H), 3.99-4.01 (m, 1H), 4.21-4.25 (m, 1H), 4.37- 4.38
(m, 1H), 4.81-4.85 (m, 1H), 5.58 (dd, J = 8.0, 4.0 Hz, 1H), 5.82-
5.95 (m, 1H), 5.96-6.09 (m, 1H), 6.10-6.13 (m, 1H), 7.18 (dd, J =
12.0, 8.0 Hz, 2H), 7.53-7.57 (m, 3H), 11.52 (s, 1H) 55 4-F--Ph H H
Me c-Hex .sup.1H NMR (DMSO-d.sub.6) .delta. 1.20-1.44 (m, 12H),
1.60-1.71 (m, 4H), 3.75- 4.02 (m, 2H), 3.94-4.02 (m, 1H), 4.19-4.26
(m, 2H), 4.59-4.61 (m, 1H), 5.57 (t, J = 8.4 Hz, 1H), 5.85-6.06 (m,
3H), 7.17-7.23 (m, 4H), 7.54 (d, J = 8.4 Hz, 1H), 11.50 (s, 1H);
MS, m/e 587.92 (M + 1).sup.+ 56 4-Br--Ph H H Me c-Hex .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. = 1.18-1.46 (m, 12H), 1.61-1.69
(m, 4H), 3.75-3.82 (m, 2H), 3.95-4.08 (m, 1H), 4.25-4.28 (m, 1H),
4.38 (s, 1H), 4.60-4.62 (m, 1H), 5.56-5.60 (m, 1H), 5.82-5.95 (m,
1H), 6.02- 6.20 (m, 2H), 7.09-7.20 (m, 2H), 7.53-7.57 (m, 3H),
11.52 (s, 1H) MS, m/e 650.0 (M + 3).sup.+ 57 Ph H H Et i-Pr .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. = 0.75-0.82 (m, 3H), 1.12-1.26
(m, 9H), 1.52-1.59 (m, 2H), 3.55-3.68 (m, 1H), 3.72-3.85 (m, 1H),
3.95- 4.08 (m, 1H), 4.18-4.28 (m, 1H), 4.32-4.41 (m, 1H), 4.83-4.86
(m, 1H), 5.55 (m, J = 7.6 Hz, 1H), 5.99-6.04 (m, 2H), 6.05-6.10 (m,
1H), 7.14-7.21 (m, 3H), 7.33-7.37 (m, 2H), 7.52-7.54 (m, 1H), 11.53
(s, 1H); MS, m/e 566.07 (M + 23).sup.+ 58 Ph H H Et c-Hex .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 0.75-0.88 (m, 3H), 1.26-1.46
(m, 9H), 1.52-1.69 (m, 6H), 3.60-3.63 (m, 1H), 3.72-3.90 (m, 1H),
4.02- 4.03 (m, 1H), 4.24-4.27 (m, 1H), 4.37-4.38 (m, 1H), 4.63-4.65
(m, 1H), 5.55 (dd, J = 8.0 Hz, 4.4 Hz, 1H), 5.80-5.95 (m, 1H),
6.00-6.07 (m, 2H), 7.15-7.22 (m, 3H), 7.34-7.38 (m, 2H), 7.54 (d, J
= 8.0 Hz, 1H), 11.55 (s, 1H); MS, m/e 584.01 (M + 1).sup.+, 606.17
(M + 23).sup.+ 59 4-F--Ph H H Et c-Hex .sup.1H NMR (DMSO-d.sub.6)
.delta. 0.75-0.84 (m, 3H), 1.24 (d, J = 22.8 Hz, 3H), 1.29-1.47 (m,
6H), 1.51-1.70 (m, 6H), 3.59-3.66 (m, 1H), 3.77-3.84 (m, 1H),
3.98-4.04 (m, 1H), 4.21-4.27 (m, 1H), 4.34-4.41 (m, 1H), 4.60-4.65
(m, 1H), 5.56-5.60 (m, 1H), 5.84-5.90 (m, 1H), 6.00-6.08 (m, 2H),
7.20-7.24 (m, 4H), 7.56 (d, J = 8.0 Hz, 1H), 11.49 (s, 1H); MS, m/e
602.00 (M + 1).sup.+ 60 Ph H H Me F--CH.sub.2--CH.sub.2 .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.18-1.25 (m, 6H), 3.71-3.89 (m, 2H),
3.92-3.99 (m, 1H), 4.19-4.27 (m, 4H), 4.48-4.61 (m, 2H), 3.94-3.98
(m, 2H), 4.11-4.23 (m, 4H), 5.47-5.52 (m, 1H), 6.01-6.11 (m, 1H),
5.90-6.14 (m, 2H), 7.15-7.21 (m, 3H), 7.32-7.36 (m, 2H), 7.46-7.57
(m, 1H), 11.49 (s, 1H); MS, m/e 533.86 (M + 1).sup.+ 61 Ph H H Me
F.sub.2CH--CH.sub.2-- .sup.1H NMR (DMSO-d.sub.6) .delta. 1.17-1.24
(m, 6H), 3.67-3.81 (m, 1H), 3.89- 3.98 (m, 2H), 4.21-4.36 (m, 4H),
5.48-5.53 (m, 1H), 5.82-6.05 (m, 2H), 6.18-6.22 (m, 2H), 7.15-7.20
(m, 3H), 7.32-7.36 (m, 2H), 7.51 (s, 1H), 11.50 (s, 1H); MS, m/e
551.92 (M + 1).sup.+; 62 Ph H H Me (CF.sub.3).sub.2--CH-- .sup.1H
NMR (DMSO-d.sub.6) .delta. 1.13-1.29 (m, 6H), 3.67-3.81 (m, 1H),
3.94- 4.32 (m, 4H), 5.47 (t, J = 8 Hz 1H), 5.82-6.01 (m, 2H),
6.33-6.36 (m, 1H), 6.70-6.78 (m, 1H), 7.09-7.15 (m, 3H), 7.28-7.32
(m, 2H), 7.43- 7.46 (m, 1H), 11.44 (s, 1H); MS, m/e 637.90 (M +
1).sup.+ 63 Ph H H Me (CH.sub.2F).sub.2--CH-- .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.20-1.29 (m, 6H), 3.70-3.90 (m, 1H), 3.91-
4.12 (m, 2H), 4.20-4.33 (m, 1H), 4.35-4.48 (m, 1H), 4.52-4.55 (m,
2H), 4.63-4.67 (m, 2H), 5.20-5.35 (m, 1H), 5.56 (t, J = 8.4 Hz,
1H), 5.80-5.95 (m, 1H), 5.95-6.10 (m, 1H), 6.18-6.21 (m, 1H),
7.18-7.23 (m, 3H), 7.35-7.39 (m, 2H), 7.54 (s, 1H), 11.55 (s, 1H);
MS, m/e 565.98 (M + 1).sup.+ 64 Ph H H Me c-Pr--CH.sub.2-- .sup.1H
NMR (DMSO-d.sub.6) .delta. 0.20-0.24 (m, 2H), 0.47-0.48 (m, 2H),
0.76- 0.84 (m, 3H), 1.03-1.05 (m, 1H), 1.23 (dd, J = 22.4 6.8 Hz
3H), 1.55- 1.60 (m, 2H), 3.61-3.68 (m, 1H), 3.81-3.89 (m, 3H),
3.98-4.03 (m, 1H), 4.23-4.29 (m, 1H), 4.35-4.41 (m, 1H), 5.56-6.00
(m, 1H), 5.88-5.91 (m, 1H), 6.04-6.10 (m, 2H), 7.20-7.24 (m, 4H),
7.55 (d, J = 7.6 Hz 1H), 11.53 (s, 1H); MS, m/e 573.17 (M +
1).sup.+ 65 Ph H H Et c-Pen .sup.1H NMR (DMSO-d.sub.6) .delta.
0.75-0.83 (m, 3H), 1.20-1.28 (m, 3H), 1.49- 1.63 (m, 8H), 1.76-1.80
(m, 2H), 3.58-3.60 (m, 1H), 3.70-3.82 (m, 1H), 3.98-4.05 (m, 1H),
4.24-4.26 (m, 1H), 4.37-4.42 (m, 1H), 5.03 (s, 1H), 5.54-5.57 (m,
1H), 5.90-6.00 (m, 1H), 6.02-6.07 (m, 2H), 7.15- 7.22 (m, 3H),
7.35-7.39 (m, 2H) 7.55 (d, J = 8.0 Hz, 1H), 11.55 (s, 1H); MS, m/e
570.03 (M + 1).sup.+ *R.sup.2 and R.sup.3b together are
--(CH.sub.2).sub.3-- as derived from L-proline
The Purification Procedure by Prep-HPLC:
[0866] Crude products were dissolved in methanol. Injection volumes
of these solutions were 5 mL.
[0867] The preparative HPLC system including 2 sets of Gilson 306
pumps, a Gilson 156 UV/Vis detector, a Gilson 215 injector &
fraction collector, with Unipoint control software. A Ymc
25.times.30.times.2 mm column was used. The mobile phase was HPLC
grade water (A), and HPLC grade acetonitrile (B). Fractions were
collected into 100*15 mm glass tubes.
[0868] HPLC gradient is shown in Table 1. Once the gradient was
selected, acetonitrile solution was injected into HPLC system, and
then fractions collected according to UV peaks. After the
separation, each glass tubes were run MS test to collect the
desired compounds. The fractions with target MS were combined in a
well-weighted flask. Most of acetonitrile was removed under reduce
pressure and the remaining solution was freeze-dried to give
desired compound.
TABLE-US-00033 TABLE 1 Preparative HPLC gradient Time (min) Flow
rate (mL/min) % A % B 0 15 90 10 30 15 60 40
Preparation of Example 66
##STR00033## ##STR00034##
[0869] Preparation of Compound (b)
[0870] To a solution of compound a (1 g, 2.69 mmol) in anhydrous
THF (30 mL) was added dropwise 1 M solution of LiAl(OBu-t).sub.3H
in THF (2.69 mL, 2.69 mmol) at -20.degree. C. The reaction mixture
was stirred for 2-3 h at the same temperature. EtOAc (100 mL) was
added followed by saturated NH.sub.4Cl solution (10 mL) and
reaction mixture was slowly brought to room temperature. Reaction
mixture was extracted with EtOAc and washed with 1N HCl and water.
Combined organic phase was evaporated to give 0.8 g of crude
compound b as transparent oil, which was used directly for next
reaction.
Preparation of Compound (d)
[0871] To a solution of compound b (0.8 g, 2.1 mmol), compound c
(0.45 g, 2.5 mmol) and Ph.sub.3P (0.56 g, 2.1 mmol) in anhydrous
THF (20 mL) under nitrogen atmosphere was added DEAD (1.8 mL). The
reaction mixture was stirred at room temperature overnight. The
reaction solution was concentrated under reduce pressure. The
residue was separated by preparative layer chromatography
(hexanes:EtOAc=3:1) to give crude compound d (0.8 g). The crude
compound d was used to the next step without further
purification.
Preparation of Compound (e)
[0872] Compound d (0.8 g, 1.57 mmol) was dissolved in THF (2 mL)
and THF saturated with ammonia (5 mL) was then added to this
solution. The reaction mixture was heated to 90.degree. C.
overnight. After 18 hours, the solution was cooled to room
temperature by ice water, then the solvent was removed under
reduced pressure and the residue was purified by column to give
compound e (0.75 g) for the next step.
Preparation of Compound (f)
[0873] Compound e (0.5 g, 1.01 mmol) was dissolved in methanol (2
mL) and methanol was saturated with ammonia (5 mL) was then added
to this solution. The reaction mixture was stirred at room
temperature overnight. After 18 hours, the solvent was removed
under reduced pressure and the residue was purified by column to
give crude compound f (0.15 g) for the next step.
Preparation of Compound (i)
[0874] A solution of triethylamine (1.07 g, 10.6 mmol) in anhydrous
dichloromethane (15 mL) was added dropwise to a solution of
compound g (1.16 g, 5.3 mmol) and compound h (1.31 g, 5.3 mmol) in
dichloromethane (10 mL) with vigorous stirring at -78.degree. C.
over a period of 2 hours. After completion of addition, the
reaction temperature was allowed to warm to room temperature
gradually and stirred over night. Then the solvent was removed
under vacuum and anhydrous ether 20 mL was added and the
precipitated salt was filtered and the precipitate was washed with
ether. The combined organic phase was concentrated to give the
colorless oil of compound i (1.0 g).
Preparation of Compound 66
[0875] To a solution of compound j (0.1 g, 0.35 mmol) dissolved in
10 mL of anhydrous THF, stirred and added 0.4 g NMI till the
solution became clear, added compound i (0.8 g, 2.89 mmol) in 10 mL
THF dropwise, stirred at r.t. overnight. Compound purity and
identification was confirmed by LCMS. The solvent was evaporated
and purified by Prep-HPLC to afford 66. (25 mg, Yield: 13.6%).
.sup.1H NMR (DMSO-d.sub.6) .delta. 1.08 (d, J=22.8 Hz, 3H),
1.17-1.24 (m, 3H), 3.50-3.52 (m, 3H), 3.78-3.83 (m, 1H), 4.10-4.13
(m, 1H), 4.24-4.44 (m, 2H), 5.85-5.92 (m, 1H), 6.01-6.11 (m, 1H),
6.2.-6.27 (m, 1H), 7.08-7.19 (m, 4H), 7.31-7.38 (m, 3H), 8.15 (s,
1H), 8.26 (s, 1H); MS, m/e 525 (M+1).sup.+.
Example numbers 67-74, identified below, were prepared using
similar procedures disclosed for Example 66, above.
TABLE-US-00034 ##STR00035## Example R.sup.11 R.sup.10 NMR/MS 67 OH
NH.sub.2 .sup.1H NMR(DMSO-d.sub.6) .delta. 1.06-1.13 (m, 3H),
1.20-1.24 (m, 3H), 3.27-3.33 (m, 3H), 3.56 (s, 1H), 3.82-3.88 (m,
1H), 4.07-4.13 (m, 1H), 4.25-4.40 (m, 2H), 5.85-5.87 (m, 1H),
5.98-6.09 (m, 2H), 6.59 (s, 32H), 7.14-7.37 (m, 3H), 7.35-7.37 (m,
2H), 7.79 (d, J = 7.2 Hz, 1H), 10.69 (s, 1H); MS, m/e 541 (M +
1).sup.+; 68 NH.sub.2 NH.sub.2 .sup.1H NMR (DMSO-d.sub.6) .delta.
1.07 (d, J = 22.8 Hz, 3H), 1.19 (d, J = 7.2 Hz, 3H), 3.51 (s, 3H),
3.62 (s, 1H), 3.75-3.81 (m, 1H), 4.05-4.11 (m, 1H), 4.27-4.42 (m,
2H), 5.79-5.83 (m, 1H), 5.92 (s, 2H), 6.00-6.09 (m, 2H), 6.75 (s,
2H), 7.08-7.17 (m, 3H), 7.31-7.35 (m, 2H), 7.78 (s, 1H); MS, m/e
540 (M + 1).sup.+; 69 NH.sub.2 c-Pentyl-NH-- .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.05 (d, J = 22.8 Hz, 3H), 1.09-1.19 (m,
3H), 1.48 (s, 4H), 1.66 (s, 1H), 1.86 (s, 1H), 3.54 (d, J = 14 Hz,
3H), 3.65 (s, 1H), 4.25-4.43 (m, 4H), 5.71-5.82 (m, 1H), 5.94-6.04
(m, 4H), 7.11-7.24 (m, 3H), 7.26-7.34 (m, 2H), 7.77 (d, J = 3.6 Hz,
1H); MS, m/e 608 (M + 1).sup.+ 70 NH.sub.2 ##STR00036## .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.07 (d, J = 22.4 Hz, 3H), 2.35-2.38 (m,
2H), 3.54 (d, J = 9.2 Hz, 3H), 3.59-3.62 (m, 2H), 3.65 (s, 1H),
3.75-3.82 (m, 1H), 4.01-4.13 (m, 2H), 4.22-4.40 (m, 6H), 5.75-5.85
(m, 1H), 6.00-6.07 (m, 4H), 7.15-7.21 (m, 3H), 7.32-7.35 (m, 2H),
7.79 (d, J = 4.0 Hz, 1H); MS, m/e 580 (M + 1).sup.+ 71 NH.sub.2
Et.sub.2N-- .sup.1H NMR (DMSO-d.sub.6) .delta. 1.06-1.28 (m, 12H),
3.55 (d, J = 4.8 Hz, 3H), 3.79-3.87 (m, 4H), 4.07-4.12 (m, 2H),
4.29-4.42 (m, 3H), 5.75-5.82 (m, 1H), 5.94 (s, 2H), 6.04-6.10 (m,
2H), 7.14-7.22 (m, 3H), 7.31-7.37 (m, 2H), 7.82 (d, J = 4.4 Hz,
1H); MS, m/e 596 (M + 1).sup.+ 72 NH.sub.2 n-Propyl-NH-- .sup.1H
NMR (DMSO-d.sub.6) .delta. 0.84 (t, J = 7.2 Hz, 3H), 1.01-1.01 (m,
3H), 1.09-1.12 (m, 3H), 1.51-1.56 (m, 2H), 3.48 (d, J = 15.2 Hz,
3H), 3.79-3.82 (m, 1H), 4.04-4.05 (m, 1H), 4.27-4.38 (m, 3H),
5.72-5.79 (m, 1H), 5.98-6.04 (m, 4H), 7.13-7.20 (m, 3H), 7.26-7.32
(m, 2H), 7.76 (d, J = 5.2 Hz, 1H); MS, m/e 582 (M + 1).sup.+ 73
NH.sub.2 c-Butyl-NH-- .sup.1H NMR (DMSO-d.sub.6) .delta. 1.02-1.08
(m, 3H), 1.18 (d, J = 4.8 Hz, 3H), 1.44-1.61 (m, 2H) , 2.02-2.17
(m, 4H), 3.51 (d, J = 10.8 Hz, 3H), 3.78-3.83 (m, 1H), 4.03-4.06
(m, 1H), 4.27-4.38 (m, 2H), 4.53-4.62 (m, 1H), 5.68-5.79 (m, 1H),
5.95-6.04 (m, 4H), 7.11-7.18 (m, 3H), 7.29-7.35 (m, 2H), 7.51-7.58
(m, 1H), 7.78 (d, J = 5.2 Hz, 1H); MS, m/e 594 (M + 1).sup.+ 74
NH.sub.2 ##STR00037## .sup.1H NMR (DMSO-d.sub.6) .delta. 0.97-1.20
(m, 6H), 2.18 (s, 3H), 2.19 (s, 4H), 3.43-3.47 (m, 3H), 3.75 (s,
1H), 4.01-4.06 (m, 4 H), 4.22-4.35 (m, 3H), 5.69-5.75 (m, 1H),
5.98-6.05 (m, 3H), 7.09-7.15 (m, 3H), 7.25-7.29 (m, 2H), 7.77 (d, J
= 3.6 Hz, 1H); MS, m/e 623 (M + 1).sup.+
[0876] Example numbers 75-80 are prepared using similar procedures
disclosed for Example 66, above.
TABLE-US-00035 ##STR00038## Example R.sup.11 R.sup.10 75 H
n-propyl--NH-- 76 H c-Butyl--NH-- 77 H c-Pentyl--NH-- 78 H
##STR00039## 79 H ##STR00040## 80 H ##STR00041##
Example 81
[0877] Certain exemplified compounds were obtained as mixture of
diastereomers because of the chirality at phosphorous. The
diastereomers were separated on a Chiralpak-AS-H (2.times.25 cm)
column under Supercritical Fluid Chromatography (SFC) conditions
using 20% methanol in carbon dioxide as solvent. The absolute
stereochemistry of the P-chiral center of the diastereromers were
not determined. However, chromatographic resolution of these two
diastereomers provides for isomers that are characterized as fast
eluting and slow eluting isomers. Some examples are shown
below.
TABLE-US-00036 Compound EC90 (uM) Example 15 (Diastereomeric
mixture) 0.86 Fast Moving isomer of Example 15 1.35 Slow Moving
isomer of Example 15 0.26 Example 39 (Diastereomeric mixture) 0.47
Fast Moving isomer of Example 39 0.78 Slow Moving isomer of Example
39 0.02 Example 49 (Diastereomeric mixture) 0.126 Fast Moving
isomer of Example 49 0.03 Slow Moving isomer of Example 49 5.78
Example 82
[0878] HCV Replicon Assay.
[0879] HCV replicon RNA-containing Huh7 cells (clone A cells;
Apath, LLC, St. Louis, Mo.) were kept at exponential growth in
Dulbecco's modified Eagle's medium (high glucose) containing 10%
fetal bovine serum, 4 mM L-glutamine and 1 mM sodium pyruvate, lx
nonessential amino acids, and G418 (1,000 .mu.g/ml). Antiviral
assays were performed in the same medium without G418. Cells were
seeded in a 96-well plate at 1,500 cells per well, and test
compounds were added immediately after seeding. Incubation time 4
days. At the end of the incubation step, total cellular RNA was
isolated (RNeasy 96 kit; Qiagen). Replicon RNA and an internal
control (TaqMan rRNA control reagents; Applied Biosystems) were
amplified in a single-step multiplex RT-PCR protocol as recommended
by the manufacturer. The HCV primers and probe were designed with
Primer Express software (Applied Biosystems) and covered highly
conserved 5'-untranslated region (UTR) sequences (sense,
5'-AGCCATGGCGTTAGTA(T)GAGTGT-3', and antisense,
5'-TTCCGCAGACCACTATGG-3'; probe,
5'-FAM-CCTCCAGGACCCCCCCTCCC-TAMRA-3').
[0880] To express the antiviral effectiveness of a compound, the
threshold RT-PCR cycle of the test compound was subtracted from the
average threshold RT-PCR cycle of the no-drug control
(.DELTA.Ct.sub.HCV). A .DELTA.Ct of 3.3 equals a 1-log 10 reduction
(equal to the 90% effective concentration [EC.sub.90]) in replicon
RNA levels. The cytotoxicity of the test compound could also be
expressed by calculating the .DELTA.Ct.sub.rRNA values. The
.DELTA..DELTA.Ct specificity parameter could then be introduced
(.DELTA.Ct.sub.HCV-.DELTA.Ct.sub.rRNA), in which the levels of HCV
RNA are normalized for the rRNA levels and calibrated against the
no-drug control.
TABLE-US-00037 Log10 Reduction at EC90 Ex # Compound 50 .mu.M
(.mu.M) 5 ##STR00042## -1.21 3.0 6 ##STR00043## -0.45 ND 7
##STR00044## 0.31 ND 8 ##STR00045## -1.48 2.11 10 ##STR00046##
-1.25 19.15 11 ##STR00047## -0.55 ND 12 ##STR00048## 0.31 ND 15
##STR00049## ND 0.86 25 ##STR00050## -2.22 0.39 27 ##STR00051##
-2.25 0.66 28 ##STR00052## -2.16 0.75 36 ##STR00053## -1.64 21.9 39
##STR00054## -1.78 0.47 49 ##STR00055## -2.69 0.126 53 ##STR00056##
-1.33 <0.3 54 ##STR00057## -1.55 0.57 55 ##STR00058## -2.38
<0.3 69 ##STR00059## -2.25 <0.3 70 ##STR00060## -2.25 <0.3
.sup.1(4-BrPh): 4-bromo--phenyl.
[0881] The entire contents of U.S. Provisional Application Nos.
60/909,315, filed Mar. 30, 2007, and 60/982,309, filed Oct. 24,
2007, are hereby incorporated by reference in the present
application so far as needed to supplement the present disclosure
and/or rectify any errors. Moreover, the patent and non-patent
references disclosed herein are incorporated by reference. In the
event that the incorporated patent and non-patent reference
contains a term that conflicts with a term disclosed in either one
of the two Provisional Applications or the present application
text, the meaning of the term contained in the present application
text and the two Provisional Applications controls provided that
the overall meaning of the incorporated subject matter is not
lost.
TABLE-US-LTS-00001 LENGTHY TABLES The patent application contains a
lengthy table section. A copy of the table is available in
electronic form from the USPTO web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20180000855A1).
An electronic copy of the table will also be available from the
USPTO upon request and payment of the fee set forth in 37 CFR
1.19(b)(3).
Sequence CWU 1
1
3123DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1agccatggcg ttagtatgag tgt 23218DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
2ttccgcagac cactatgg 18320DNAArtificial SequenceDescription of
Artificial Sequence Synthetic probe5'-FAM3'-TAMRA 3cctccaggac
cccccctccc 20
* * * * *
References